Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment

King, Lanikea B.; Walum, Hasse; Inoue, Kiyoshi; Eyrich, Nicholas W.; Young, Larry J.

doi:10.1016/j.biopsych.2015.12.008

Cited by 197Neuroendocrine regulation and behaviorNeurotransmitter Receptor Influence on BehaviorGenetics and Neurodevelopmental Disorders

Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment

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King, Lanikea B., Walum, Hasse, Inoue, Kiyoshi, Eyrich, Nicholas W., Young, Larry J.·2016·Biological Psychiatry

DOI 10.1016/j.biopsych.2015.12.008PMC PMC4909578

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Abstract

Background Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in autism spectrum disorder (ASD) and common genetic variants in the human oxytocin receptor (OXTR) are associated with emotion recognition, relationship quality and ASD. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. Methods We investigated Oxtr expression in monogamous prairie voles, which have a well characterized OXT system. We quantified brain region-specific levels of Oxtr mRNA and OXTR protein with established neuroanatomical methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. Results Our allelic imbalance data demonstrates that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens (NAcc), where OXTR signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis-regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. Discussion Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how non-coding polymorphisms in the OXTR might influence individual differences in human social cognition and behavior

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Written from the paper’s full text.

TL;DR

In prairie voles, non-coding variation in the oxytocin receptor gene predicts brain-region-specific Oxtr expression and OXTR density, especially in the nucleus accumbens. An intronic SNP, NT213739, explains at least 74% of the variance in NAcc OXTR density and is associated with mating-induced partner preference formation in males.

Key findings

Oxtr allelic imbalance was strongest in striatal regions: in heterozygous voles, the T-allele transcript was 3–5 times more prevalent than the C-allele in NAcc (cDNA ratio 3.16; gDNA threshold 1.11) and CP (cDNA ratio 5.24; gDNA threshold 1.13), with a lesser effect in amygdala (cDNA ratio 1.19; gDNA threshold 1.14).
Sequencing 70 kb around Oxtr in 45 voles identified 967 SNPs; 15 SNPs in linkage disequilibrium spanning 30 kb were associated with NAcc OXTR density at P=1.06×10−15, adjusted R²=0.78.
The intronic SNP NT213739 was robustly associated with NAcc OXTR density across independent samples (all P-values <4×10−10; adjusted R²≥74%) and with Oxtr mRNA levels; it was not associated with insular cortex OXTR density.
In the partner preference test, C/C males spent significantly more time huddling with the partner than the stranger, whereas C/T and T/T males failed to display a partner preference.

Methods

Prairie voles from a laboratory breeding colony were used for brain-region-specific measures of Oxtr mRNA and OXTR protein via in situ hybridization and autoradiography, with sample sizes including N=31 for autoradiography and N=31 for in situ hybridization.
Allelic imbalance was assayed by pyrosequencing in animals heterozygous for the 3′UTR SNP NT204321 (minor allele frequency 0.33); next-generation sequencing of 70 kb surrounding Oxtr was performed in 45 voles, followed by genotyping of NT213739 in additional samples (n=35 and n=31).
Associations between genetic markers and brain data used linear regression with Bonferroni correction, factor analysis for brain-region covariation, and PLINK/SEQ for SNP–autoradiography associations; social attachment was assessed with the partner preference test.

Limitations

The paper states that the genotype–phenotype relationships do not implicate NT213739 above other SNPs in perfect LD spanning 30 kb, and that larger samples of more genetically diverse animals, including wild-caught specimens, may be needed to break the haplotype structure and identify the functional SNP.
The paper notes that cross-species comparisons of putative regulatory elements should be interpreted cautiously because transcription factor binding sites may differ between species.
Evident from the text: the study reports strong associations but does not perform direct functional validation such as ChIP-seq, chromosome conformation capture, or in vitro transcription assays; the behavioral sample size for the partner preference test is not stated in the provided text.

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Crossref · 10.1016/j.biopsych.2015.12.008

Cites

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Claims the paper makes

0 of 89 cited sources checked · 0 supported · 0 flagged

Findingown data
Sequencing 70 kb around Oxtr in 45 voles identified 967 SNPs with read depth at least 100, quality score at least 1000, all variable in the sample.
“Amongst the 45 voles we sequenced, we identified 967 SNPs with a read depth no lower than 100 reads, a quality score of at least 1000, and for which all were variable in our sample.”
Quote in the paperNot a substantial claim
Findingown data
In heterozygous animals for NT204321, significant allelic imbalance occurred in the nucleus accumbens, caudate putamen, and to a lesser degree amygdala.
“In heterozygous animals for this SNP, we found significant allelic imbalance in NAcc (cDNA: 3.16, gDNA threshold: 1.11), caudate putamen (CP) (cDNA: 5.24, gDNA threshold: 1.13) and to a lesser degree, amygdala (Amyg) (cDNA: 1.19, gDNA threshold: 1.14).”
Quote in the paperSubstantial claim
Findingown data
A second factor analysis in an additional sample (N=85) also revealed two factors explaining most of the variance.
“We performed a second factor analysis in an additional sample (N=85) (Table 1b) and this analysis, like the first one, revealed two factors explaining most of the variance.”
Quote in the paperSubstantial claim
Findingown data
Due to linkage disequilibrium, 15 SNPs spanning 30 kb were associated with nucleus accumbens OXTR density with the same minimal P-value (P=1.06×10−15, adjusted R2=0.78).
“Due to linkage disequilibrium, 15 SNPs spanning a 30 kb region were associated with NAcc OXTR density with the same, minimal P-value (P=1.06×10−15, adjusted R2=0.78), which is a remarkable effect size for a genotype-phenotype relationship.”
Quote in the paperSubstantial claim
Findingown data
In the nucleus accumbens and caudate putamen, the T-allele transcript was 3-5 times more prevalent than the C-allele in heterozygous animals.
“The allelic imbalance was pronounced in the two striatal sub-regions, NAcc and CP, with the T-allele transcript being 3–5 times more prevalent than the C-allele in the same animals in these regions (Figure 1d).”
Quote in the paperSubstantial claim

Findingown data
In all samples, NT213739 was strongly associated with nucleus accumbens OXTR expression (all P-values <4×10−10).
“In all of our relatively small samples, NT213739 was strongly associated with NAcc expression (all P-values<4×10−10).”
Quote in the paperSubstantial claim
Findingown data
A SNP in the Oxtr 3' untranslated region, NT204321, had a minor allele frequency of 33% in the prairie vole colony.
“One SNP in the 3’ untranslated region (minor allele frequency 33%), heretofore referred to as NT204321 based on the position of this nucleotide on a sequenced prairie vole bacterial artificial clone (58) (DP001215.2), was identified using this method.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [58] Mouse, 2012, An encyclopedia of mouse DNA elements (Mouse ENCODE), Genome Biol source
  Not checked in the free run.
Findingown data
Factor analysis of OXTR density across 12 brain regions (N=31) revealed two factors explaining 58% of the variance.
“Our analysis revealed two factors together explaining the majority of variance (58%).”
Quote in the paperSubstantial claim
Findingown data
The nucleus accumbens and caudate putamen exhibited more individual variation in OXTR density than other brain regions.
“As expected based on previous experiments, the NAcc and caudate putamen (CP) exhibited more individual variation in OXTR density than other brain regions (Figure 1a–c).”
Quote in the paperSubstantial claim
Findingown data
Only one of the 15 most associated SNPs, NT213739 (minor allele frequency 0.32), overlapped with strong signatures of transcriptional function.
“Only one SNP overlapped with strong signatures of transcriptional function, a SNP occurring at nucleotide 213739 (NT213739, minor allele frequency: 0.32) (Figure 3b).”
Quote in the paperSubstantial claim
Findingown data
OXTR binding density appeared correlated with Oxtr mRNA levels based on in situ hybridization signal.
“Furthermore, OXTR binding density appeared to be correlated with Oxtr mRNA levels based on in situ hybridization signal (Figure 1a).”
Quote in the paperNot a substantial claim
Findingown data
Regions loading on Factor 1 were more related to NT204321 genotype than regions loading on Factor 2.
“We identified similar patterns when we investigated the associations between NT204321 and the OXTR expression in the 12 brain regions, with regions loading into Factor 1 being more related to genotype than those loading into Factor 2 (Figure 2).”
Quote in the paperSubstantial claim
Findingown data
The sequence containing NT213739 overlapped peaks of DNase hypersensitivity and CTCF binding within the large intron, a region proposed to contain cis-regulatory elements in humans.
“The sequence containing NT213739 overlapped peaks of DNase hypersensitivity and CTCF binding within the large intron, a region proposed to contain cis-REs in humans (20, 61, 62).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
  Not checked in the free run.
- cites [61] Liu, 2015, Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals, Human Genome Variation source
  Not checked in the free run.
- cites [62] Young, 1996, Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences, J Neuroendocrinol source
  Not checked in the free run.
Findingown data
Many SNPs across the Oxtr sequence were strongly associated with nucleus accumbens OXTR density.
“Clearly, as can be seen in Figure 3a many of the SNPs in our set were strongly associated with NAcc OXTR density.”
Quote in the paperSubstantial claim
Findingown data
Prairie vole Oxtr expression is strongly influenced by polymorphic cis-regulatory elements that include or are associated with the intronic SNP NT213739.
“We found that prairie vole Oxtr expression is strongly influenced by polymorphic cis-REs that include or are associated with NT213739, a SNP in the intron of the gene.”
Quote in the paperSubstantial claim
Findingown data
NT213739 was significantly associated with Oxtr mRNA levels in the nucleus accumbens.
“We found that NT213739 is also significantly associated with Oxtr mRNA levels in the NAcc (Figure 4b)”
Quote in the paperSubstantial claim
Findingown data
Oxtr mRNA levels and OXTR density in the nucleus accumbens were significantly correlated.
“and that mRNA levels and OXTR density were significantly correlated (Figure 4c, 4d).”
Quote in the paperSubstantial claim
Findingown data
Exploratory factor analysis identified a cluster of striatal-olfactory regions with correlated OXTR density.
“Exploratory factor analysis identified a cluster of striatal-olfactory regions with correlated OXTR density.”
Quote in the paperSubstantial claim
Findingown data
NT213739, or any SNP in perfect linkage disequilibrium with it, accounts for 74% of the variance in NAcc OXTR.
“Our data suggests that NT213739, or any of the SNPs in perfect LD with it, explain 74% of the variation in NAcc OXTR.”
Quote in the paperSubstantial claim
Findingown data
Among 15 SNPs in perfect linkage disequilibrium, only NT213739 mapped to a mouse Oxtr intron site with robust evidence of transcriptional activity.
“We focused our attention on NT213739 because out of 15 SNPs in perfect LD with one another, only NT213739 mapped to a site in the mouse Oxtr intron with robust evidence of transcriptional activity.”
Quote in the paperSubstantial claim
Findingown data
One SNP can account for most OXTR expression variance in particular brain regions.
“Here we use the prairie vole model to demonstrate for the first time that a single SNP can predict the majority of variance in OXTR expression in specific brain regions.”
Quote in the paperSubstantial claim
Premisecitation
OXTR signaling in the nucleus accumbens is required for mating-induced partner preference formation in prairie voles.
“OXTR signaling in the NAcc is required for mating-induced partner preference formation, a laboratory proxy of pair bonding (6).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
  Not checked in the free run.
Premiseown data
Infusion of an OXTR antagonist into the nucleus accumbens or prefrontal cortex, but not the caudate putamen, blocks mating-induced partner preferences in male prairie voles.
“Infusion of an OXTR antagonist into the NAcc or the PFC, but not the caudate putamen (CP) blocks mating-induced partner preferences in females (35) and males (A.C. Keebaugh and LJY, unpublished data).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites (A.C. Keebaugh and LJY, unpublished data)
  Not checked in the free run.
Premisecitation
OXTR density is much higher in the nucleus accumbens of prairie voles than in promiscuous vole species.
“OXTR density is much higher in the NAcc of prairie voles than promiscuous vole species”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
  Not checked in the free run.
Premisecitation
Infusion of an OXTR antagonist into the nucleus accumbens or prefrontal cortex, but not the caudate putamen, blocks mating-induced partner preferences in female prairie voles.
“Infusion of an OXTR antagonist into the NAcc or the PFC, but not the caudate putamen (CP) blocks mating-induced partner preferences in females (35)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [35] Olazabal, 2006, Species and individual differences in juvenile female alloparental care are associated with oxytocin receptor density in the striatum and the lateral septum, Horm Behav source
  Not checked in the free run.
Premisecitation
In prairie voles, OXTR is enriched in mesolimbic reward regions including the nucleus accumbens and prefrontal cortex, which are part of a neural network for pair bonding.
“In a socially monogamous rodent, the prairie vole (Microtus ochrogaster), OXTR is enriched in important MLR regions such as the nucleus accumbens (NAcc) and prefrontal cortex (PFC) that constitute part of a neural network for pair bonding (6, 8, 34).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
  Not checked in the free run.
- cites [8] Johnson, 2015, Neural networks involved in social attachment and pair bonding, Curr Opin Behav Sci source
  Not checked in the free run.
- cites [34] Young, 2001, Cellular mechanisms of social attachment, Horm Behav source
  Not checked in the free run.
Premisecitation
Increasing OXTR density in the nucleus accumbens using viral-vector mediated gene transfer facilitates partner preference formation.
“Increasing OXTR density in the NAcc using viral-vector mediated gene transfer facilitates partner preference formation, while decreasing OXTR density in the same region using RNA interference inhibits such bonding (37–39).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [37] Keebaugh, 2011, Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults, Horm Behav source
  Not checked in the free run.
- cites [38] Keebaugh, 2015, RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles, Soc Neurosci source
  Not checked in the free run.
- cites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
  Not checked in the free run.
Premisecitation
Variation in prairie vole nucleus accumbens OXTR confers susceptibility or resilience to the effects of daily neonatal isolations on adult social attachment ability.
“Furthermore, variation in prairie vole NAcc OXTR confers susceptibility or resilience to the effects of daily neonatal isolations, a model of neglect, in relation to the ability to form social attachments as adults (41).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [41] Wittkopp, 2012, Cis-regulatory elements: Molecular mechanisms and evolutionary processes underlying divergence, Nat Rev Genet source
  Not checked in the free run.
Premisecitation
Variation in nucleus accumbens OXTR density is correlated with individual differences in monogamy-related behavior in male prairie voles in naturalistic settings.
“Variation in NAcc OXTR density is correlated with individual differences in monogamy-related behavior in males in naturalistic settings (40).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [40] Barrett, 2015, The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles, Transl Psychiatry source
  Not checked in the free run.
Premisecitation
OXTR density varies between individual prairie voles, especially in the nucleus accumbens and caudate putamen.
“OXTR density also varies between individual prairie voles, especially in the NAcc along with the CP (36).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [36] Ross, 2009, Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles, J Neurosci source
  Not checked in the free run.
Premisecitation
Decreasing OXTR density in the nucleus accumbens using RNA interference inhibits partner preference formation.
“Increasing OXTR density in the NAcc using viral-vector mediated gene transfer facilitates partner preference formation, while decreasing OXTR density in the same region using RNA interference inhibits such bonding (37–39).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [37] Keebaugh, 2011, Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults, Horm Behav source
  Not checked in the free run.
- cites [38] Keebaugh, 2015, RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles, Soc Neurosci source
  Not checked in the free run.
- cites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
  Not checked in the free run.
Interpretationown data
The allelic imbalance data suggest that cis-regulatory elements linked to NT204321 generate individual variation in Oxtr expression in select brain tissues.
“These data strongly suggest that cis-REs linked to NT204321 generate individual variation in expression of Oxtr in select brain tissues.”
Quote in the paperSubstantial claim
Study design and conductown data
The current genotype-phenotype relationships do not single out NT213739 over the other SNPs in perfect linkage disequilibrium across the 30 kb.
“it is important to note that our current genotype-phenotype relationships do not implicate NT213739 above any of the other SNPs in perfect LD with it spanning the 30 kb.”
Quote in the paperNot a substantial claim
Premisecitation
In the NAcc, OXTR activation is required for prairie vole partner preference formation.
“In a key region of the MLR, the NAcc, OXTR activation is necessary for prairie vole partner preference formation (35)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [35] Olazabal, 2006, Species and individual differences in juvenile female alloparental care are associated with oxytocin receptor density in the striatum and the lateral septum, Horm Behav source
  Not checked in the free run.
Interpretationreasoning
Transcription factor(s) leading to the covariation appear to interact with cis-regulatory elements associated with NT213739 to generate high variation in expression in these regions but not others.
“Whatever transcription factor or factors leads to the covariation appear to interact with the cis-REs associated with NT213739 to generate the high variation in expression observed in these regions, but not other regions.”
Quote in the paperSubstantial claim
Premisecitation
CTCF binding peaks occur in the intron and near the promoter of both mouse Oxtr and human OXTR.
“as CTCF binding peaks are found in the intron as well as near the promoter of both the mouse Oxtr (Figure 3b) and human OXTR (20).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
  Not checked in the free run.
Premisecitation
Differences in pair bonding behavior are mediated by OXTR variation.
“and OXTR variation mediates individual differences in pair bonding behaviors (37–39).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [37] Keebaugh, 2011, Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults, Horm Behav source
  Not checked in the free run.
- cites [38] Keebaugh, 2015, RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles, Soc Neurosci source
  Not checked in the free run.
- cites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
  Not checked in the free run.
Premisecitation
In some rodent brain regions, OXTR expression is regulated by gonadal steroids in a species-specific manner.
“In some rodent brain regions, OXTR expression is regulated by gonadal steroids in a species specific manner.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [68] Bale, 1995, Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites, Endocrinology source
  Not checked in the free run.
- cites [69] Odom, 2007, Tissue-specific transcriptional regulation has diverged significantly between human and mouse, Nat Genet source
  Not checked in the free run.
Interpretationreasoning
Brain phenotype measured directly should yield larger effect sizes than behavioral studies report.
“Thus direct measures of brain phenotype are likely to yield stronger effect sizes than reported in behavioral studies.”
Quote in the paperSubstantial claim
- Rests on an assumption: Candidate gene polymorphisms usually explain only 1–10% of behavioral phenotype variance in behavioral genetic studies.
- The authors state this as an assumption: OXTR density lies closer to genotype than behavior does in biological terms.
- The authors state this as an assumption: Behavioral genetic studies usually involve many additional contributors to behavioral variation.
Premisecitation
Human studies have linked intronic OXTR variants to individual differences in functional connectivity among brain regions while processing social information.
“Recent research in humans found that intronic OXTR variants predicted individual differences in functional connectivity between brain regions during the processing of social information (80, 81).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [80] Tost, 2011, Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults, Biol Psychiatry source
  Not checked in the free run.
- cites [81] Parker, 2014, Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder, Proc Natl Acad Sci U S A source
  Not checked in the free run.
Premisecitation
A recent meta-analysis concludes that OXTR genetic variation is linked to ASD diagnosis.
“A recent meta-analysis supports the conclusion that genetic variation in OXTR is associated with ASD diagnosis (21)”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [21] LoParo, 2015, The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis, Mol Psychiatry source
  Not checked in the free run.
Interpretationcitation
The study confirms a genetic contribution of naturally occurring OXTR density differences to individual variation in social behavior.
“Here, we confirm a genetic role for naturally occurring OXTR density differences that contribute to individual variation in social behavior (36, 40).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [36] Ross, 2009, Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles, J Neurosci source
  Not checked in the free run.
- cites [40] Barrett, 2015, The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles, Transl Psychiatry source
  Not checked in the free run.
Interpretationreasoning
The findings point to a possible conserved function of OXTR in social cognition across species, even though expression sites likely differ.
“These results highlight a potentially conserved role for OXTR in social cognition between species despite likely differences in sites of expression.”
Quote in the paperSubstantial claim
Premisecitation
During pair bond formation in prairie voles, OXTR signaling boosts functional connectivity across a network of regions.
“In addition to region-specific effects, OXTR signaling enhances functional connectivity within a network of regions during prairie vole pair bond formation (79).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [79] Tost, 2010, A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function, Proc Natl Acad Sci U S A source
  Not checked in the free run.
Interpretationown data
The present study suggests that polymorphisms in OXTR cis-regulatory elements, acting in a brain-region-specific way, may mediate these genotype-phenotype relationships.
“The present study suggests that these genotype-phenotype relationships may be mediated by polymorphisms in cis-REs in the OXTR gene that influence OXTR density in a brain region-specific manner.”
Quote in the paperSubstantial claim

May combine two claims. 23
Classified as probably not a substantial claim. 19

May combine two claims.
Findingown data
Nucleus accumbens OXTR binding was almost perfectly correlated with Factor 1, and insular cortex binding was close to perfectly correlated with Factor 2.
“OXTR binding in the NAcc was almost perfectly correlated with the first factor and binding in the insular cortex (Ins) was close to perfectly correlated with Factor 2.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
In two additional samples (n=35, n=31), NT213739 was robustly associated with OXTR density in the nucleus accumbens but not the insular cortex.
“After genotyping additional voles (Sample 2 n=35, Sample 3 n=31) for NT213739, we confirmed the SNP was robustly associated with OXTR density in the NAcc but not in the Ins (Figure 4a).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Factor 1 reflected co-variability among reward-processing regions (nucleus accumbens, caudate putamen, olfactory tubercle), while Factor 2 reflected covariation among cortical and subcortical regions with relatively uniform OXTR density.
“Factor 1 strongly reflects co-variability in a set of regions involved in reward processing (NAcc, CP, and olfactory tubercle) while the second factor reflects covariation between cortical and subcortical regions that have relatively uniform levels of OXTR density (Table 1a).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Nucleus accumbens OXTR density values did not overlap between homozygotes for the two NT213739 genotypes, and heterozygotes had an intermediate phenotype.
“The effect was marked, such that OXTR density values in the NAcc between homozygous animals of the two genotypes did not overlap at all while heterozygous animals displayed an intermediate phenotype.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The effect size of NT213739 on nucleus accumbens OXTR expression was large in all samples (adjusted R2≥74%), suggesting it explains at least 74% of the variance.
“Similarly, the effect size of this association was very large in all samples (adjusted R2≥74%), strongly suggesting that NT213739 explains at least 74% of the variance in NAcc expression of OXTR in prairie voles.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Allelic imbalance is strongest in the striatum and genotype-OXTR associations are most robust in this region.
“Allelic imbalance is strongest in the striatum and genotype-OXTR associations are most robust in this region.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
There was a significant effect of NT213739 genotype on partner preference formation: C/C males spent significantly more time huddling with the partner than the stranger, while C/T and T/T males did not display a partner preference.
“There was a significant effect of genotype on partner preference formation, with C/C voles spending significantly more time huddling with the partner than the stranger, while C/T and T/T males failed to display a partner preference (Figure 5).”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim. May combine two claims.
Premisecitation
Noncoding SNPs in the human OXTR are associated with pair bonding, parenting, face recognition, and autism.
“Single nucleotide polymorphisms (SNPs) in noncoding regions of the human OXTR have been associated with pair bonding behaviors (19), parenting (1), face recognition skills (20), and autism (21).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [19] Walum, 2012, Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior, Biol Psychiatry source
  Not checked in the free run.
- cites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
  Not checked in the free run.
- cites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
OXTR is distributed throughout the brain of many vertebrates, and its distribution pattern differs between species.
“OXTR is distributed throughout the brain of many vertebrates and, importantly, the pattern of OXTR distribution is diverse between species (32, 33).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
  Not checked in the free run.
- cites [33] Freeman, 2014, The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta), Psychoneuroendocrinology source
  Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation
Some individuals show heterogeneous responses to oxytocin, which may involve interaction with OXTR genetic polymorphisms.
“Some individuals have heterogeneous responses to OXT (22, 23), which may involve interaction with OXTR genetic polymorphisms (24–27).”
Quote in the paperSubstantial claim0 of 6 sources checked
- cites [22] Bartz, 2011, Social effects of oxytocin in humans: Context and person matter, Trends Cogn Sci
  Not checked in the free run.
- cites [23] Olff, 2013, The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences, Psychoneuroendocrinology source
  Not checked in the free run.
- cites [24] Marsh, 2012, The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype, Psychopharmacology source
  Not checked in the free run.
- cites [25] Montag, 2013, An interaction between oxytocin and a genetic variation of the oxytocin receptor modulates amygdala activity toward direct gaze: Evidence from a pharmacological imaging genetics study, Eur Arch Psychiatry Clin Neurosci source
  Not checked in the free run.
- cites [26] Chen, 2015, Genetic modulation of oxytocin sensitivity: A pharmacogenetic approach, Transl Psychiatry source
  Not checked in the free run.
- cites [27] Feng, 2015, A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans, Genes Brain Behav source
  Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation
Oxytocin receptor signaling influences several social behaviors in animals, including maternal care and bonding, social reward and gregariousness, social recognition, and pair bonding in monogamous species.
“OXTR affects a range of social behaviors in animals including maternal nurturing and bonding (1, 2), social reward and gregariousness (3, 4), social recognition (5), and pair bonding in monogamous species (6–8).”
Quote in the paperSubstantial claim0 of 7 sources checked
- cites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
  Not checked in the free run.
- cites [2] Numan, 2016, Neural mechanisms of mother-infant bonding and pair bonding: Similarities, differences, and broader implications, Horm Behav source
  Not checked in the free run.
- cites [3] Dolen, 2013, Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin, Nature source
  Not checked in the free run.
- cites [4] Goodson, 2009, Mesotocin and nonapeptide receptors promote estrildid flocking behavior, Science source
  Not checked in the free run.
- cites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
  Not checked in the free run.
- cites [7] Goodson, 2012, Evolving nonapeptide mechanisms of gregariousness and social diversity in birds, Horm Behav source
  Not checked in the free run.
- cites [8] Johnson, 2015, Neural networks involved in social attachment and pair bonding, Curr Opin Behav Sci source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation.
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28–31).”
Quote in the paperNot a substantial claim0 of 4 sources checked
- cites [28] Loth, 2014, Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events, Biol Psychiatry source
  Not checked in the free run.
- cites [29] Lucas-Thompson, 2013, Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress, Horm Behav source
  Not checked in the free run.
- cites [30] Smearman, 2015, Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an at-risk cohort, Dev Psychopathol source
  Not checked in the free run.
- cites [31] Thompson, 2011, Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls, Psychoneuroendocrinology source
  Not checked in the free run.
May combine two claims.
Premisecitation
OXTR is often enriched in regions of crucial behavioral circuits such as the mesolimbic reward network and social decision-making network, and appears to modulate these networks to generate species-specific social strategies such as monogamous social attachments and social gregarity.
“OXTR is often enriched within regions of crucial behavioral circuits such as the mesolimbic reward (MLR) network and social decision making network and appears to modulate these networks to generate species-specific social strategies such as monogamous social attachments (32) and social gregarity (7).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
  Not checked in the free run.
- cites [7] Goodson, 2012, Evolving nonapeptide mechanisms of gregariousness and social diversity in birds, Horm Behav source
  Not checked in the free run.
May combine two claims.
Premisereasoning
Differences in mRNA levels between alleles occur in the same nuclear environment, so environmental, hormonal, or epigenetic factors should affect both alleles equally unless nearby cis-regulatory elements are variable.
“Any differences in mRNA levels between alleles occur in the same nuclear environment, where both alleles should be affected equally by environmental, hormonal or epigenetic factors, unless cis-REs proximal to the alleles are variable.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Premisecitation
Allelic imbalance is commonly observed in a tissue-specific manner.
“Allelic imbalance is commonly observed in a tissue-specific manner (51, 52).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [51] Wilkins, 2007, Extreme context specificity in differential allelic expression, Hum Mol Genet source
  Not checked in the free run.
- cites [52] Li, 2009, Fast and accurate short read alignment with Burrows-Wheeler transform, Bioinformatics source
  Not checked in the free run.
May combine two claims.
Premisecitation
In prairie voles, a microsatellite in the 5' flanking region of Avpr1a containing cis-regulatory elements has functional influence over species differences and individual variation in Avpr1a expression and is associated with variation in social behavior.
“In prairie voles, a microsatellite in the 5’ flanking region of the vasopressin receptor gene (Avpr1a) containing cis-REs has been shown to have functional influence over species differences and individual variation in Avpr1a expression and is associated with variation in social behavior (47, 48).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [47] Donaldson, 2013, The relative contribution of proximal 5′ flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior, PLoS Genet source
  Not checked in the free run.
- cites [48] Johnson, 2005, Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics, Pharmacol Ther source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Variation in gene expression mediated by cis-regulatory elements plays an important role in evolutionary phenotypic change.
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42–46).”
Quote in the paperNot a substantial claim0 of 6 sources checked
- cites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
  Not checked in the free run.
- cites [42] Bendesky, 2011, Genetic contributions to behavioural diversity at the gene-environment interface, Nat Rev Genet source
  Not checked in the free run.
- cites [43] Linnen, 2013, Adaptive evolution of multiple traits through multiple mutations at a single gene, Science source
  Not checked in the free run.
- cites [44] Oleksiak, 2002, Variation in gene expression within and among natural populations, Nat Genet source
  Not checked in the free run.
- cites [45] Cretekos, 2008, Regulatory divergence modifies limb length between mammals, Genes Dev source
  Not checked in the free run.
- cites [46] Hammock, 2005, Microsatellite instability generates diversity in brain and sociobehavioral traits, Science source
  Not checked in the free run.
May combine two claims.
Premisecitation
Comparisons of about 1500 bp of 5' flanking regions from the Oxtr gene reveal only a few SNPs and 99% homology between prairie and montane voles.
“Comparisons of ~1500 bp of 5’ flanking regions from the Oxtr gene reveal only a few SNPs and 99% homology between the species (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [63] Young, 1997, The 5′ flanking region of the monogamous prairie vole oxytocin receptor gene directs tissue-specific expression in transgenic mice, Ann N Y Acad Sci source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
Sequencing variants were filtered to have read depth no lower than 100 reads and quality score at least 1000.
“Amongst the 45 voles we sequenced, we identified 967 SNPs with a read depth no lower than 100 reads, a quality score of at least 1000, and for which all were variable in our sample.”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
Transgenic mice carrying a reporter gene driven by 5 kb of prairie vole Oxtr 5' flanking sequence express the reporter in a brain pattern resembling prairie voles, suggesting the sequence may suffice for some aspects of brain-region-specific expression.
“Transgenic mice carrying a reporter gene driven by 5 kb of the prairie vole Oxtr 5’ flanking sequence express the reporter in the brain in a pattern resembling prairie voles (64), suggesting the sequence may suffice for some aspects of brain region-specific expression.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [64] Harony-Nicolas, 2014, Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation, Psychoneuroendocrinology source
  Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation
Polymorphic cis-regulatory elements have been shown to affect CTCF binding and DNA looping.
“Polymorphic cis-REs have been shown to influence CTCF binding (71, 72) and DNA looping (73).”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [71] Paredes, 2013, Allele-specific transcriptional activity of the variable number of tandem repeats in 5′ region of the DRD4 gene is stimulus specific in human neuronal cells, Genes Brain Behav source
  Not checked in the free run.
- cites [72] Visser, 2015, Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter, Hum Mol Genet source
  Not checked in the free run.
- cites [73] Dekker, 2013, Exploring the three-dimensional organization of genomes: Interpreting chromatin interaction data, Nat Rev Genet source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
The human OXTR intron accumulates rare SNPs in ASD cases.
“and accumulates rare SNPs in cases of ASD (62).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [62] Young, 1996, Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences, J Neuroendocrinol source
  Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation
CTCF acts as a spatial organizer, helping DNA loop so cis-regulatory elements can interact with promoters for gene transcription.
“One role of CTCF is to act as a spatial organizer, aiding DNA looping to permit cis-RE-promoter interactions required for gene transcription (60).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [60] Mizumoto, 1997, A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression, Mol Cell Endocrinol source
  Not checked in the free run.
May combine two claims.
Interpretationown data
Together these data suggest NT213739 is strongly associated with transcriptional variation of Oxtr and tightly linked to a cis-regulatory element.
“Together these data suggest that NT213739 is strongly associated with transcriptional variation of the Oxtr gene and tightly linked to a cis-RE.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
DNA methylation of OXTR in humans may be mediated by an intronic SNP.
“Interestingly, DNA methylation of OXTR in humans may be mediated by an intronic SNP (67).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [67] Insel, 1993, Gonadal steroids have paradoxical effects on brain oxytocin receptors, J Neuroendocrinol source
  Not checked in the free run.
May combine two claims.
Interpretationreasoning
cis-regulatory elements appear to contribute exquisite control over OXTR and through this process influence behavioral diversity in prairie voles.
“In this manner cis-REs appear to contribute exquisite control over OXTR and through this process, influence behavioral diversity in prairie voles.”
Quote in the paperSubstantial claim
May combine two claims.
Premisecitation
Prairie voles show strong OXTR expression in MLR regions, a conserved reward-processing network implicated in depression, addiction, and schizophrenia.
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (75) involved in reward processing and implicated in numerous human psychiatric disorders including depression (76), addiction (77), and schizophrenia (78).”
Quote in the paperNot a substantial claim0 of 3 sources checked
- cites [75] Russo, 2013, The brain reward circuitry in mood disorders, Nat Rev Neurosci source
  Not checked in the free run.
- cites [76] Luscher, 2011, Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling, Neuron source
  Not checked in the free run.
- cites [77] Abi-Dargham, 2014, Schizophrenia: Overview and dopamine dysfunction, J Clin Psychiatry source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
The human OXTR intron may contain additional cis-regulatory elements.
“Additionally, the human intron may contain other cis-REs (61)”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [61] Liu, 2015, Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals, Human Genome Variation source
  Not checked in the free run.
May combine two claims.
Interpretationown data
Genetic variation in Oxtr exerts robust control over individual diversity in Oxtr expression and OXTR density in the prairie vole brain, and this influence is region-specific.
“We here demonstrate that genetic variation in the Oxtr exerts robust control over individual diversity in Oxtr expression and OXTR density in the prairie vole brain and that this influence on expression occurs in a region-specific manner.”
- Also stated in: § Discussion · boosted
  “Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
DNA-binding sites for transcription factors can vary across species.
“We note that such comparisons should be made with the understanding that transcription factor binding sites may differ between species (70).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [70] Verlaan, 2009, Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease, Am J Hum Genet source
  Not checked in the free run.
May combine two claims.
Premisecitation
Within the third intron of human OXTR, a CTCF peak is close to SNP rs237887, predicted to lie near a cis-regulatory element and linked to face recognition and ASD diagnosis.
“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE, and associated with face recognition abilities (20) and ASD diagnosis (21).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
  Not checked in the free run.
- cites [21] LoParo, 2015, The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis, Mol Psychiatry source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice.
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (68, 69).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [68] Bale, 1995, Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites, Endocrinology source
  Not checked in the free run.
- cites [69] Odom, 2007, Tissue-specific transcriptional regulation has diverged significantly between human and mouse, Nat Genet source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Factor extraction decisions were based on the eigenvalues-greater-than-one rule, parallel analysis, the optimal coordinates method, and the acceleration factor.
“Regarding the factor analyses, to determine how many factors to extract we used the “nFactors” package in R and the factor extraction decisions were based on the eigenvalues-greater-than-one rule, parallel analysis, the optimal coordinates method and acceleration factor.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
DNA methylation of Oxtr differs between brain regions in rodents.
“DNA methylation of Oxtr differs between brain regions in rodents (65, 66).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [65] Beery, 2016, Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats, Horm Behav source
  Not checked in the free run.
- cites [66] Reiner, 2015, Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype, J Psychiatr Res source
  Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown data
Associations between genetic information and brain data were examined using linear regression with Bonferroni corrections for multiple comparisons.
“Associations between genetic information and brain data were examined using linear regression with Bonferroni corrections for multiple comparisons.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Other studies report links between OXTR and ASD endophenotypes, such as structural differences in social-cognition brain regions.
“and others have reported associations with endophenotypes of ASD (20, 82, 83), including structural variability in brain regions relevant to social cognition (80, 84).”
Quote in the paperNot a substantial claim0 of 3 sources checked
- cites [20] Skuse, 2014, Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills, Proc Natl Acad Sci U S A source
  Not checked in the free run.
- cites [82] Lerer, 2008, Association between the oxytocin receptor (OXTR) gene and autism: Relationship to Vineland Adaptive Behavior Scales and cognition, Mol Psychiatry source
  Not checked in the free run.
- cites [83] Inoue, 2010, Association between the oxytocin receptor gene and amygdalar volume in healthy adults, Biol Psychiatry source
  Not checked in the free run.

36 of 36

The paper relies on this without support.
The neural mechanisms by which non-coding SNPs in OXTR influence behavior have not yet been explored.
“Despite these many associations with human social behavior and disorders, the neural mechanisms by which non-coding SNPs in the OXTR could influence behaviors has yet to be explored.”
The authors state this as an assumption.
Correlations between OXTR densities across brain regions can be explained by unobserved latent variables, possibly reflecting transcriptional processes.
“We hypothesize that correlations between OXTR densities from different brain regions can be explained by unobserved variables, possibly reflecting transcriptional processes giving rise to the patterns of correlation.”
The paper relies on this without support.
Mouse ENCODE signatures of transcriptional activity in the Oxtr region indicate homologous cis-regulatory elements in prairie vole.
“we investigated their homology with regions of the mouse Oxtr gene that overlap with signatures of functional activity occurring within neural tissues where OXTR is expressed in the mouse (59).”
The paper relies on this without support.
Candidate gene polymorphisms usually explain only 1–10% of behavioral phenotype variance in behavioral genetic studies.
“Behavioral genetic studies typically report that 1–10% of the variance in behavioral phenotype is explained by candidate gene polymorphisms.”
The authors state this as an assumption.
OXTR density lies closer to genotype than behavior does in biological terms.
“We presume that OXTR density is biologically more proximate to genotype than behavior”
The authors state this as an assumption.
Behavioral genetic studies usually involve many additional contributors to behavioral variation.
“and in typical behavioral genetic studies many more variables are contributing to behavioral variation.”

6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Male C/C prairie voles display enhanced social attachment as compared to C/T and T/T animals.
“These genetic variations may also influence social behavior, as male C/C prairie voles display enhanced social attachment as compared to C/T and T/T animals [71].”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [71]
The striatum and regions within the midbrain are highly populated with oxytocin receptors in non-human animals.
“it is well known from non-human animal work that the striatum and regions within the midbrain are highly populated with oxytocin receptors.44, 45”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [45]
Individual differences in nucleus accumbens oxytocin receptor density in prairie voles are mediated by a single nucleotide polymorphism in a regulatory region of the oxytocin receptor gene.
“Furthermore, individual differences in the density of OXTR in the NAcc in prairie voles have now been shown to be mediated by a single nucleotide polymorphism (SNP) in a regulatory region of the OXTR gene (22)”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [22]
Prairie voles with high nucleus accumbens oxytocin receptor levels show enhanced social attachment.
“and individuals with high NAcc OXTR show enhanced social attachment (22)”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [22]
OXTR polymorphisms in the prairie vole robustly predict individual differences in OTR density in the NAc as well as pair bonding behavior.
“However, it is important to note that OXTR polymorphisms in the prairie vole robustly predict individual differences in OTR density in the NAc as well as pair bonding behavior (King et al., 2016).”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as King et al., 2016

Site-specific OTR blockade does not likely reflect natural intra- and interspecific variation in levels of region-specific OTR expression and signaling.
“Finally, site-specific OTR blockade does not likely reflect natural intra- and interspecific variation in levels of region-specific OTR expression and signaling (King et al., 2016).”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as King et al., 2016
Partner preference formation in male prairie voles is predicted by a natural genetic polymorphism in the OTR gene that influences the density of OTR binding in the NAc.
“Partner preference formation in male prairie voles is predicted by a natural genetic polymorphism in the OTR gene (Oxtr) that robustly influences the density of OTR binding in the NAc”
From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as King et al. 2016
OTR density in the striatum, robustly predicted by polymorphisms in the OTR gene, is indicative of resilience to early-life social isolation with respect to later life bonding.
“Our results in prairie voles reveal that OTR density in the striatum, which is robustly predicted by polymorphisms in the OTR gene (King et al. 2016), is indicative of resilience to early-life social isolation with respect to later life bonding.”
From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as King et al. 2016
Variation in OXTR density in the nucleus accumbens is determined by genetic variation in the Oxtr gene, which in turn predicts how early-life nurturing experience affects later-life bonding ability.
“This variation in OXTR density in the NAcc is determined by genetic variation in the Oxtr gene (144), which in turn predicts how early-life nurturing experience affects laterlife bonding ability (143).”
From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [144]
In prairie voles, sequence variation determines individual variation in striatal oxytocin receptor density.
“In prairie voles, for instance, such sequence variation determines individual variation in striatal oxytocin receptor density [12]”
From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [12]
Variation in brain receptor distribution is determined by sequence variation in the receptor genes.
“This variation in brain receptor distribution is determined by sequence variation in the receptor genes [12,13].”
From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [12]
Individual variability in oxytocin receptor density within the prairie vole ventral striatum is the result of gene polymorphisms in the oxytocin receptor gene.
“Importantly, our group has recently demonstrated that the density of OTR variability between individuals within the prairie vole species in the ventral striatum is the result of gene polymorphisms in the OTR gene (King et al. 2016).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as King et al. 2016

Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · cited 1× · see citing works
“2) (53), including marking duplicate reads and local realignment around insertions/deletions.”
The variant call format and VCFtools
Danecek, P., Auton, A., Abecasis, G. R., Albers, C. A., Banks, E., DePristo, M. A., Handsaker, R. E., Lunter, G. A., Marth, G., Sherry, S. T., et al. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr330 · Cited by 16,008 · see citing works
The brain reward circuitry in mood disorders
Russo, S. J., & Nestler, E. J. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3381 · Cited by 1,870 · cited 1× · see citing works
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (74) involved in reward processing and implicated in numerous human psychiatric disorders, including depression (75), addiction (76), and schizophrenia (77).”
Oxytocin, vasopressin, and the neurogenetics of sociality
Donaldson, Z. R., & Young, L. J. (2008) · Science · doi:10.1126/science.1158668 · Cited by 1,645 · cited 2× · see citing works
“The OXTR is distributed throughout the brain of many vertebrates, and the pattern of OXTR distribution is diverse among species (32,33).”
Self-citation
Social effects of oxytocin in humans: context and person matter
Bartz, J. A., Zaki, J., Bolger, N., & Ochsner, K. N. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.05.002 · Cited by 1,572 · cited 1× · see citing works
“Some individuals have heterogeneous responses to OXT (22,23), which may involve interaction with OXTR genetic polymorphisms (24–27).”
The neurobiology of pair bonding.
Young, L. J., & Wang, Z. (2004) · Nature Neuroscience · doi:10.1038/nn1327 · Cited by 1,523 · cited 2× · see citing works
“The OXTR density is much higher in the NAc of prairie voles than promiscuous vole species, and OXTR signaling in the NAc is required for mating-induced partner preference formation, a laboratory proxy of pair bonding (6).”
Cis-regulatory elements: Molecular mechanisms and evolutionary processes underlying divergence
Wittkopp, P. J., & Kalay, G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3095 · Cited by 1,231 · cited 1× · see citing works
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin
Dölen, G., Darvishzadeh, A., Huang, K. W., & Malenka, R. C. (2013) · Nature · doi:10.1038/nature12518 · Cited by 1,161 · see citing works
Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling
Lüscher, C., & Malenka, R. C. (2011) · Neuron · doi:10.1016/j.neuron.2011.01.017 · Cited by 1,105 · cited 1× · see citing works
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (74) involved in reward processing and implicated in numerous human psychiatric disorders, including depression (75), addiction (76), and schizophrenia (77).”
Exploring the three-dimensional organization of genomes: Interpreting chromatin interaction data
Dekker, J., Marti-Renom, M. A., & Mirny, L. A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3454 · Cited by 1,068 · cited 1× · see citing works
“Furthermore, biochemical analyses, including chromatin immunoprecipitation followed by sequencing, chromosome conformation capture (73), and in vitro transcription assays could be used to investigate interactions between CTCF binding, DNA looping, and Oxtr regulation.”
CTCF: an architectural protein bridging genome topology and function
Ong, C., & Corces, V. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3663 · Cited by 1,044 · cited 2× · see citing works
“modification of lysine 27 on H3 histone (green); H3K4m1, single methyl modific the transcription factor CCCTC-binding factor (CTCF), which can act as a canonical transcription factor or as an organizer of genomic architecture (59).”
The Challenge of Translation in Social Neuroscience: A Review of Oxytocin, Vasopressin, and Affiliative Behavior
Insel, T. R. (2010) · Neuron · doi:10.1016/j.neuron.2010.03.005 · Cited by 1,044 · cited 1× · see citing works
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Oxytocin in the Medial Amygdala is Essential for Social Recognition in the Mouse
Ferguson, J. N., Aldag, J. M., Insel, T. R., & Young, L. J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-20-08278.2001 · Cited by 1,043 · cited 1× · see citing works
“The OXTR affects a range of social behaviors in animals, including maternal nurturing and bonding (1,2), social reward and gregariousness (3,4), social recognition (5), and pair bonding in monogamous species (6–8).”
Self-citation
The Vertebrate mesolimbic reward system and social behavior network: A comparative synthesis
O'Connell, L. A., & Hofmann, H. A. (2011) · Journal of Comparative Neurology · doi:10.1002/cne.22735 · Cited by 986 · cited 1× · see citing works
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (74) involved in reward processing and implicated in numerous human psychiatric disorders, including depression (75), addiction (76), and schizophrenia (77).”
Promoting social behavior with oxytocin in high-functioning autism spectrum disorders.
Andari, E., Duhamel, J.-R., Zalla, T., Herbrecht, E., Leboyer, M., & Sirigu, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910249107 · Cited by 941 · cited 1× · see citing works
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Variation in gene expression within and among natural populations
Oleksiak, M. F., Churchill, G. A., & Crawford, D. L. (2002) · Nature Genetics · doi:10.1038/ng983 · Cited by 736 · cited 1× · see citing works
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
The role of oxytocin in social bonding, stress regulation and mental health: an update on the moderating effects of context and interindividual differences
Olff, M., Frijling, J. L., Kubzansky, L. D., Bradley, B., Ellenbogen, M. A., Cardoso, C., Bartz, J. A., Yee, J. R., & van Zuiden, M. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.06.019 · Cited by 620 · cited 1× · see citing works
“heterogeneous responses to OXT (22, 23), which may involve interaction with OXTR genetic”
Genomic and epigenetic evidence for oxytocin receptor deficiency in autism
Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., Lintas, C., Abramson, R. K., Wright, H. H., Ellis, P., et al. (2009) · BMC Medicine · doi:10.1186/1741-7015-7-62 · Cited by 576 · see citing works
A common allele in the oxytocin receptor gene ( OXTR ) impacts prosocial temperament and human hypothalamic-limbic structure and function
Tost, H., Kolachana, B., Hakimi, S., Lemaitre, H., Verchinski, B. A., Mattay, V. S., Weinberger, D. R., & Meyer–Lindenberg, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003296107 · Cited by 564 · cited 2× · see citing works
“Research in humans found that intronic OXTR variants predicted individual differences in functional connectivity between brain regions during the processing of social information (79,80).”
Microsatellite instability generates diversity in brain and sociobehavioral traits
Hammock, E. A. D., & Young, L. J. (2005) · Science · doi:10.1126/science.1111427 · Cited by 545 · cited 1× · see citing works
“In prairie voles, a microsatellite in the 50 flanking region of the vasopressin receptor gene (Avpr1a) containing cis-REs has been shown to have functional influence over species differences and individual variation in Avpr1a expression and is associated with variation in social behavior (46,47).”
Self-citation
Cellular Mechanisms of Social Attachment
Young, L. J., Lim, M. M., Gingrich, B., & Insel, T. R. (2001) · Hormones and Behavior · doi:10.1006/hbeh.2001.1691 · Cited by 523 · cited 2× · see citing works
“In a key region of the MLR, the NAc, OXTR activation is necessary for prairie vole partner preference formation (34), and OXTR variation mediates individual differences in pair bonding behaviors (36–38).”
Self-citation
Tissue-specific transcriptional regulation has diverged significantly between human and mouse
Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., & Fraenkel, E. (2007) · Nature Genetics · doi:10.1038/ng2047 · Cited by 506 · cited 1× · see citing works
“Such comparisons should be made with the understanding that transcription factor binding sites may differ among species (69).”
The biology of mammalian parenting and its effect on offspring social development
Rilling, J. K., & Young, L. J. (2014) · Science · doi:10.1126/science.1252723 · Cited by 452 · cited 4× · see citing works
“The OXTR affects a range of social behaviors in animals, including maternal nurturing and bonding (1,2), social reward and gregariousness (3,4), social recognition (5), and pair bonding in monogamous species (6–8).”
InfluentialSelf-citation
An encyclopedia of mouse DNA elements (Mouse ENCODE)
Mouse ENCODE Consortium, Stamatoyannopoulos, J. A., Snyder, M., Hardison, R., Ren, B., Gingeras, T., Gilbert, D. M., Groudine, M., Bender, M., Kaul, R., et al. (2012) · Genome Biology · doi:10.1186/gb-2012-13-8-418 · Cited by 446 · cited 1× · see citing works
“To assess whether any of the 15 most associated SNPs are more likely than others to lie in a putative cis-RE, we investigated their homology with regions of the mouse Oxtr gene that overlap with signatures of functional activity occurring within neural tissues where OXTR is expressed in the mouse (58).”
Sniffing around oxytocin: Review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.34 · Cited by 383 · cited 1× · see citing works
“In humans, intranasal OXT reportedly enhances many aspects of social cognition, including trust, emotion recognition, and eye gaze (1, 10).”
Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism
Peñagarikano, O., Lázaro, M. T., Lu, X.-H., Gordon, A., Dong, H., Lam, H. A., Peles, E., Maidment, N. T., Murphy, N. P., Yang, X. W., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.3010257 · Cited by 378 · cited 1× · see citing works
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Neural mechanisms of mother–infant bonding and pair bonding: Similarities, differences, and broader implications
Numan, M., & Young, L. J. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.015 · Cited by 355 · cited 2× · see citing works
“The OXTR affects a range of social behaviors in animals, including maternal nurturing and bonding (1,2), social reward and gregariousness (3,4), social recognition (5), and pair bonding in monogamous species (6–8).”
Self-citation
Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition
Lerer, E., Levi, S., Salomon, S., Darvasi, A., Yirmiya, N., & Ebstein, R. P. (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002087 · Cited by 349 · cited 4× · see citing works
“Nevertheless, the OXT system is a leading candidate target for improving social function in patients with psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (12–17), and one report suggested that OXTR expression may be reduced in ASD (18).”
Influential
Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies
Walum, H., Waldman, I. D., & Young, L. J. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.06.016 · Cited by 345 · cited 1× · see citing works
“Individual reports of the effects of intranasal OXT should be interpreted cautiously (11).”
Self-citation
The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis
LoParo, D., & Waldman, I. D. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.77 · Cited by 343 · cited 6× · see citing works
“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE and associated with face recognition abilities (20) and ASD diagnosis (21).”
Influential
Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles
Ross, H. E., Freeman, S. M., Spiegel, L. L., Ren, X., Terwilliger, E. F., & Young, L. J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5039-08.2009 · Cited by 322 · cited 1× · see citing works
“OXTR autoradiography was performed as previously reported (36).”
Self-citation
Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease
Verlaan, D. J., Berlivet, S., Hunninghake, G. M., Madore, A.-M., Larivière, M., Moussette, S., Grundberg, E., Kwan, T., Ouimet, M., Ge, B., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.08.007 · Cited by 297 · cited 1× · see citing works
“Polymorphic cis-REs have been shown to influence CTCF binding (70,71) and DNA looping (72).”
Adaptive evolution of multiple traits through multiple mutations at a single gene
Linnen, C. R., Poh, Y.-P., Peterson, B. K., Barrett, R. D. H., Larson, J. G., Jensen, J. D., & Hoekstra, H. E. (2013) · Science · doi:10.1126/science.1233213 · Cited by 292 · cited 1× · see citing works
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system
Kumsta, R., & Heinrichs, M. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.09.004 · Cited by 265 · cited 1× · see citing works
“Such findings in humans call for a better understanding of molecular mechanisms regulating OXTR variation (21,84).”
Mesotocin and nonapeptide receptors promote estrildid flocking behavior
Goodson, J. L., Schrock, S. E., Klatt, J. D., Kabelik, D., & Kingsbury, M. A. (2009) · Science · doi:10.1126/science.1174929 · Cited by 241 · cited 1× · see citing works
“OXTR affects a range of social behaviors in animals including maternal nurturing and bonding (1, 2), social reward and gregariousness (3, 4), social recognition (5), and pair”
Regulatory divergence modifies limb length between mammals
Cretekos, C. J., Wang, Y., Green, E. D., Program, N. C. S., Martin, J. F., Rasweiler, J. J., & Behringer, R. R. (2008) · Genes & Development · doi:10.1101/gad.1620408 · Cited by 232 · cited 1× · see citing works
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
Species and individual differences in juvenile female alloparental care are associated with oxytocin receptor density in the striatum and the lateral septum
Olazábal, D. E., & Young, L. J. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2005.12.010 · Cited by 230 · cited 2× · see citing works
“The OXTR density also varies among individual prairie voles, especially in the NAc and the CP (35).”
Self-citation
The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies
Modi, M. E., & Young, L. J. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.12.010 · Cited by 218 · cited 2× · see citing works
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Self-citation
Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder
Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C.-P., Phillips, J. M., Hallmayer, J. F., & Hardan, A. Y. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402236111 · Cited by 215 · cited 4× · see citing works
“Nevertheless, the OXT system is a leading candidate target for improving social function in patients with psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (12–17), and one report suggested that OXTR expression may be reduced in ASD (18).”
Influential
Variation in the Oxytocin Receptor Gene Is Associated with Pair-Bonding and Social Behavior
Walum, H., Lichtenstein, P., Neiderhiser, J. M., Reiss, D., Ganiban, J. M., Spotts, E. L., Pedersen, N. L., Anckarsäter, H., Larsson, H., & Westberg, L. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.09.002 · Cited by 211 · cited 1× · see citing works
“Single nucleotide polymorphisms (SNPs) in noncoding regions of the human OXTR have been associated with pair bonding behaviors (19), parenting (1), face recognition skills (20), and autism (21).”
Self-citation
Oxytocin Receptor Gene Polymorphism (rs2254298) Interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls
Thompson, R. J., Parker, K. J., Hallmayer, J. F., Waugh, C. E., & Gotlib, I. H. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.07.003 · Cited by 211 · cited 1× · see citing works
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
Common polymorphism in the oxytocin receptor gene ( OXTR ) is associated with human social recognition skills
Skuse, D. H., Lori, A., Cubells, J. F., Lee, I., Conneely, K. N., Puura, K., Lehtimäki, T., Binder, E. B., & Young, L. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1302985111 · Cited by 207 · cited 5× · see citing works
“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE and associated with face recognition abilities (20) and ASD diagnosis (21).”
InfluentialSelf-citation
Can oxytocin treat autism?
Young, L. J., & Barrett, C. E. (2015) · Science · doi:10.1126/science.aaa8120 · Cited by 200 · see citing works
Self-citation
Central oxytocin receptors mediate mating-induced partner preferences and enhance correlated activation across forebrain nuclei in male prairie voles
Johnson, Z. V., Walum, H., Jamal, Y. A., Xiao, Y., Keebaugh, A. C., Inoue, K., & Young, L. J. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.11.011 · Cited by 190 · cited 1× · see citing works
“In addition to region-specific effects, OXTR signaling enhances functional connectivity within a network of regions during prairie vole pair bond formation (78).”
Self-citation
The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta)
Freeman, S. M., Inoue, K., Smith, A. L., Goodman, M. M., & Young, L. J. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.023 · Cited by 185 · cited 1× · see citing works
“The OXTR is distributed throughout the brain of many vertebrates, and the pattern of OXTR distribution is diverse among species (32,33).”
Neurobiological mechanisms of social attachment and pair bonding
Johnson, Z. V., & Young, L. J. (2015) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2015.01.009 · Cited by 169 · see citing works
Self-citation
Association between the oxytocin receptor gene and amygdalar volume in healthy adults
Inoue, H., Yamasue, H., Tochigi, M., Abe, O., Liu, X., Kawamura, Y., Takei, K., Suga, M., Yamada, H., Rogers, M. A., et al. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.07.019 · Cited by 164 · cited 1× · see citing works
“A recent meta-analysis supports the conclusion that genetic variation in OXTR is associated with diagnosis of ASD (21), and other authors have reported associations with endophenotypes of ASD (20,81,82), including structural variability in brain regions relevant to social cognition (79,83).”
Oxytocin receptor density is associated with male mating tactics and social monogamy
Ophir, A. G., Gessel, A., Zheng, D.-J., & Phelps, S. M. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.01.007 · Cited by 161 · cited 2× · see citing works
“Variation in NAc OXTR density is correlated with individual differences in monogamy-related behavior in males in naturalistic settings (39).”
Digital RNA allelotyping reveals tissue-specific and allele-specific gene expression in human
Zhang, K., Li, J. B., Gao, Y., Egli, D. M., Xie, B., Deng, J., Li, Z., Lee, J., Aach, J., LeProust, E. M., et al. (2009) · Nature Methods · doi:10.1038/nmeth.1357 · Cited by 156 · cited 1× · see citing works
“Allelic imbalance is commonly observed in a tissue-specific manner (50,51).”
Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults
Keebaugh, A. C., & Young, L. J. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.07.018 · Cited by 154 · cited 2× · see citing works
“MLR, the NAcc, OXTR activation is necessary for prairie vole partner preference formation (35) and OXTR variation mediates individual differences in pair bonding behaviors (37-39).”
RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles
Keebaugh, A. C., Barrett, C. E., Laprairie, J. L., Jenkins, J. J., & Young, L. J. (2015) · Social Neuroscience · doi:10.1080/17470919.2015.1040893 · Cited by 150 · cited 2× · see citing works
“MLR, the NAcc, OXTR activation is necessary for prairie vole partner preference formation (35) and OXTR variation mediates individual differences in pair bonding behaviors (37-39).”
Self-citation
Evolving nonapeptide mechanisms of gregariousness and social diversity in birds
Goodson, J. L., Kelly, A. M., & Kingsbury, M. A. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.01.005 · Cited by 139 · cited 1× · see citing works
“Within regions of crucial behavioral circuits such as the mesolimbic reward (MLR) network and social decision making network, OXTR is often enriched and appears to modulate these networks to generate speciesspecific social strategies, such as monogamous social attachments (32) and social gregariousness (7).”
Schizophrenia: Overview and Dopamine Dysfunction
Abi-Dargham, A. (2014) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.13078tx2c · Cited by 128 · cited 1× · see citing works
“Prairie voles strongly express OXTR in regions of the MLR, a conserved neural network (74) involved in reward processing and implicated in numerous human psychiatric disorders, including depression (75), addiction (76), and schizophrenia (77).”
The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles
Barrett, C. E., Arambula, S. E., & Young, L. J. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.73 · Cited by 115 · cited 1× · see citing works
“Furthermore, variation in prairie vole NAc OXTR confers susceptibility or resilience to the effects of daily neonatal isolations, a model of neglect, in relation to the ability to form social attachments as adults (40).”
Self-citation
Gonadal steroids have paradoxical effects on brain oxytocin receptors
Insel, T. R., Young, L., Witt, D. M., & Crews, D. (1993) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1993.tb00531.x · Cited by 113 · cited 1× · see citing works
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (67,68).”
Self-citation
Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences
Young, L. J., Huot, B., Nilsen, R., Wang, Z., & Insel, T. R. (1996) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1996.05188.x · Cited by 110 · cited 1× · see citing works
“Comparisons of 1500 bp of 50 flanking regions from the Oxtr gene reveal only a few SNPs and 99% homology between the species (62).”
Self-citation
Genetic contributions to behavioural diversity at the gene-environment interface
Bendesky, A., & Bargmann, C. I. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3065 · Cited by 103 · cited 1× · see citing works
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics
JOHNSON, A., WANG, D., & SADEE, W. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.11.001 · Cited by 97 · cited 1× · see citing works
“The influence of cis-REs can be detected by assaying for allelic imbalance, which is observed when two alleles of a gene in a heterozygous individual are expressed at different rates, creating an imbalance in the respective mRNAs (49-51).”
A common oxytocin receptor gene (<scp>OXTR</scp>) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans
Feng, C., Lori, A., Waldman, I. D., Binder, E. B., Haroon, E., & Rilling, J. K. (2015) · Genes, Brain and Behavior · doi:10.1111/gbb.12234 · Cited by 94 · see citing works
The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype
Marsh, A. A., Yu, H. H., Pine, D. S., Gorodetsky, E. K., Goldman, D., & Blair, R. J. R. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2775-0 · Cited by 87 · see citing works
Research progress in allele-specific expression and its regulatory mechanisms
Gaur, U., Li, K., Mei, S., & Liu, G. (2013) · Journal of Applied Genetics · doi:10.1007/s13353-013-0148-y · Cited by 84 · cited 1× · see citing works
“The influence of cis-REs can be detected by assaying for allelic imbalance, which is observed when two alleles of a gene in a heterozygous individual are expressed at different rates, creating an imbalance in the respective mRNAs (49-51).”
Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype
Reiner, I., Van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Bleich, S., Beutel, M., & Frieling, H. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.03.012 · Cited by 83 · cited 1× · see citing works
“DNA methylation of OXTR in humans may be mediated by an intronic SNP (66).”
Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the Prairie Vole
Modi, M. E., Inoue, K., Barrett, C. E., Kittelberger, K. A., Smith, D. G., Landgraf, R., & Young, L. J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.35 · Cited by 82 · see citing works
Self-citation
Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats
Beery, A. K., McEwen, L. M., MacIsaac, J. L., Francis, D. D., & Kobor, M. S. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.022 · Cited by 81 · cited 1× · see citing works
“DNA methylation of Oxtr differs between brain regions in rodents (64,65).”
A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression
Mizumoto, Y., Kimura, T., & Ivell, R. (1997) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(97)00195-0 · Cited by 79 · cited 2× · see citing works
“The sequence containing NT213739 overlapped peaks of deoxyribonuclease hypersensitivity and CTCF binding within the large intron, a region proposed to contain cisREs in humans (20,60,61).”
Evaluation of two automated metrics for analyzing partner preference tests
Ahern, T. H., Modi, M. E., Burkett, J. P., & Young, L. J. (2009) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2009.06.010 · Cited by 79 · cited 1× · see citing works
“The partner preference was performed as previously described (55).”
Self-citation
Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults
Tost, H., Kolachana, B., Verchinski, B. A., Bilek, E., Goldman, A. L., Mattay, V. S., Weinberger, D. R., & Meyer-Lindenberg, A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.06.034 · Cited by 77 · cited 1× · see citing works
“Research in humans found that intronic OXTR variants predicted individual differences in functional connectivity between brain regions during the processing of social information (79,80).”
Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites
Bale, T. L., & Dorsa, D. M. (1995) · Endocrinology · doi:10.1210/endo.136.11.7588251 · Cited by 65 · cited 1× · see citing works
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (68, 69).”
Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events
Loth, E., Poline, J.-B., Thyreau, B., Jia, T., Tao, C., Lourdusamy, A., Stacey, D., Cattrell, A., Desrivières, S., Ruggeri, B., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.043 · Cited by 65 · cited 1× · see citing works
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
Oxytocin, social cognition and psychiatry
Young, L. J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.186 · Cited by 64 · cited 1× · see citing works
“It has been proposed that OXT influences these complex social behaviors by increasing the salience and reinforcing value of social stimuli (9).”
Self-citation
Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation
Harony-Nicolas, H., Mamrut, S., Brodsky, L., Shahar-Gold, H., Barki-Harrington, L., & Wagner, S. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.10.004 · Cited by 61 · cited 1× · see citing works
“DNA methylation of Oxtr differs between brain regions in rodents (64,65).”
Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an at-risk cohort
Smearman, E. L., Winiarski, D. A., Brennan, P. A., Najman, J., & Johnson, K. C. (2015) · Development and Psychopathology · doi:10.1017/s0954579414000649 · Cited by 60 · cited 1× · see citing works
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
Fez1 is layer‐specifically expressed in the adult mouse neocortex
Inoue, K., Terashima, T., Nishikawa, T., & Takumi, T. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03763.x · Cited by 59 · cited 1× · see citing works
“Sense and antisense (35)S-UTP–labeled RNA probes for prairie vole Oxtr mRNA were generated as described previously (54).”
Self-citation
Genetic modulation of oxytocin sensitivity: A pharmacogenetic approach
Chen, F. S., Kumsta, R., Dvorak, F., Domes, G., Yim, O. S., Ebstein, R. P., & Heinrichs, M. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.163 · Cited by 59 · see citing works
Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter
Visser, M., Palstra, R.-J., & Kayser, M. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv029 · Cited by 57 · cited 1× · see citing works
“Polymorphic cis-REs have been shown to influence CTCF binding (70,71) and DNA looping (72).”
Extreme context specificity in differential allelic expression
Wilkins, J. M., Southam, L., Price, A. J., Mustafa, Z., Carr, A., & Loughlin, J. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddl488 · Cited by 53 · cited 1× · see citing works
“Allelic imbalance is commonly observed in a tissue-specific manner (51, 52).”
The relative contribution of proximal 5′ flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior
Donaldson, Z. R., & Young, L. J. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003729 · Cited by 52 · cited 1× · see citing works
“In prairie voles, a microsatellite in the 50 flanking region of the vasopressin receptor gene (Avpr1a) containing cis-REs has been shown to have functional influence over species differences and individual variation in Avpr1a expression and is associated with variation in social behavior (46,47).”
Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress
Lucas-Thompson, R. G., & Holman, E. A. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.02.015 · Cited by 51 · cited 1× · see citing works
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
An interaction between oxytocin and a genetic variation of the oxytocin receptor modulates amygdala activity toward direct gaze: Evidence from a pharmacological imaging genetics study
Montag, C., Sauer, C., Reuter, M., & Kirsch, P. (2013) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-013-0452-x · Cited by 32 · see citing works
The 5′ flanking region of the monogamous prairie vole oxytocin receptor gene directs tissue-specific expression in transgenic mice
YOUNG, L. J., WAYMIRE, K. G., NILSEN, R., MACGREGOR, G. R., WANG, Z., & INSEL, T. R. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb51955.x · Cited by 20 · cited 1× · see citing works
“the reporter in the brain in a pattern resembling prairie voles (64), suggesting the sequence may suffice for some aspects of brain region-specific expression.”
Self-citation
Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals
Liu, X., Kawashima, M., Miyagawa, T., Otowa, T., Latt, K. Z., Thiri, M., Nishida, H., Sugiyama, T., Tsurusaki, Y., Matsumoto, N., et al. (2015) · Human Genome Variation · doi:10.1038/hgv.2015.24 · Cited by 18 · cited 5× · see citing works
“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE and associated with face recognition abilities (20) and ASD diagnosis (21).”
Influential
BAC-Based Sequencing of Behaviorally-Relevant Genes in the Prairie Vole
McGraw, L. A., Davis, J. K., Thomas, P. J., Program, N. C. S., Young, L. J., & Thomas, J. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029345 · Cited by 15 · cited 1× · see citing works
“One SNP in the 3’ untranslated region (minor allele frequency 33%), heretofore referred to as NT204321 based on the position of this nucleotide on a sequenced prairie vole bacterial artificial clone (58) (DP001215.”
Self-citation
Allele‐specific transcriptional activity of the variable number of tandem repeats in 5′ region of the <scp>DRD4</scp> gene is stimulus specific in human neuronal cells
Paredes, U. M., Quinn, J. P., & D'Souza, U. M. (2013) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00857.x · Cited by 10 · cited 1× · see citing works
“Polymorphic cis-REs have been shown to influence CTCF binding (70,71) and DNA looping (72).”

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Oxytocin, Neural Plasticity, and Social Behavior
Froemke, R. C., & Young, L. J. (2021) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-102320-102847 · Cited by 487 · see citing works
“For example, there is robust individual genetically determined variation in oxytocin receptor density in prairie vole nucleus accumbens (King et al. 2016).”
BackgroundSelf-citation
Is oxytocin “nature’s medicine”
Carter, C. S., Kenkel, W. M., MacLean, E. L., Wilson, S. R., Perkeybile, A. M., Yee, J. R., Ferris, C. F., Nazarloo, H. P., Porges, S. W., Davis, J. M., et al. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019398 · Cited by 394 · see citing works
“A reduction or upregulation in the availability of the oxytocin or vasopressin receptors can reflect both heritable genetic variation (King et al., 2016; Baker et al., 2017) and/or epigenetic tuning (Okhovat et al.”
Background
The neural mechanisms and circuitry of the pair bond
Walum, H., & Young, L. J. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0072-6 · Cited by 353 · see citing works
Self-citation
Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience
Johnson, Z. V., & Young, L. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.034 · Cited by 242 · see citing works
“Also in prairie voles, polymorphisms in Oxtr predict OTR xpression in the nucleus accumbens (NAc) and individual variaion in pair bonding (King et al., 2016).”
Self-citation
Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications
Freeman, S. M., & Young, L. J. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12382 · Cited by 196 · see citing works
“Furthermore, individual differences in the density of OXTR in the NAcc in prairie voles have now been shown to be mediated by a single nucleotide polymorphism (SNP) in a regulatory region of the OXTR gene (22), and individuals with high NAcc OXTR show enhanced social attachment (22) and resilience to early life stress…”
BackgroundSelf-citation
Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities
Rigney, N., de Vries, G. J., Petrulis, A., & Young, L. J. (2022) · Endocrinology · doi:10.1210/endocr/bqac111 · Cited by 191 · see citing works
Self-citation
Central oxytocin receptors mediate mating-induced partner preferences and enhance correlated activation across forebrain nuclei in male prairie voles
Johnson, Z. V., Walum, H., Jamal, Y. A., Xiao, Y., Keebaugh, A. C., Inoue, K., & Young, L. J. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.11.011 · Cited by 190 · see citing works
Self-citation
Molecular Basis of Oxytocin Receptor Signalling in the Brain: What We Know and What We Need to Know
Busnelli, M., & Chini, B. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_6 · Cited by 161 · see citing works
Oxytocin and Social Relationships: From Attachment to Bond Disruption
Bosch, O. J., & Young, L. J. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_10 · Cited by 162 · see citing works
“Partner preference formation in male prairie voles is predicted by a natural genetic polymorphism in the OTR gene (Oxtr) that robustly influences the density of OTR binding in the NAc (King et al. 2016).”
BackgroundSelf-citation
Early nurture epigenetically tunes the oxytocin receptor
Perkeybile, A. M., Carter, C. S., Wroblewski, K. L., Puglia, M. H., Kenkel, W. M., Lillard, T. S., Karaoli, T., Gregory, S. G., Mohammadi, N., Epstein, L., et al. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.08.037 · Cited by 160 · see citing works
Overview of human oxytocin research
Kendrick, K. M., Guastella, A. J., & Becker, B. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_19 · Cited by 121 · see citing works
Oxytocin receptors modulate a social salience neural network in male prairie voles
Johnson, Z. V., Walum, H., Xiao, Y., Riefkohl, P. C., & Young, L. J. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.10.009 · Cited by 113 · see citing works
“Finally, site-specific OTR blockade does not likely reflect natural intra- and interspecific variation in levels of region-specific OTR expression and signaling (King et al., 2016).”
Self-citation
Oxytocin pathways in the intergenerational transmission of maternal early life stress
Töpfer, P., Heim, C. C., Entringer, S., Binder, E. B., Wadhwa, P. D., & Buß, C. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.026 · Cited by 114 · see citing works
“Moreover, a highly relevant study in rodents recently showed that a polymorphism in the Oxtr gene explains a large proportion of variance in accumbal OTR expression, which is known to be functionally relevant for attachment formation and parenting (King et al., 2015).”
Background
Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression
Danoff, J. S., Wroblewski, K. L., Graves, A. J., Quinn, G. C., Perkeybile, A. M., Kenkel, W. M., Lillard, T. S., Parikh, H. I., Golino, H. F., Gregory, S. G., et al. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01017-5 · Cited by 85 · see citing works
“S3A, W = 77, p = 0.98) or NT213739 genotype (Additional file 1: Fig.”
BackgroundResultInfluential
Oxytocin receptor is not required for social attachment in prairie voles
Berendzen, K. M., Sharma, R., Alvarado, M., Wei, Y., Rogers, F. D., Simmons, T. C., Seelke, A. M. H., Bond, J. M., Larios, R., Goodwin, N. L., et al. (2023) · Neuron · doi:10.1016/j.neuron.2022.12.011 · Cited by 120 · see citing works
Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women
Bethlehem, R. A. I., Lombardo, M. V., Lai, M.-C., Auyeung, B., Crockford, S. K., Deakin, J., Soubramanian, S., Sule, A., Kundu, P., Voon, V, et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.72 · Cited by 96 · see citing works
“known from non-human animal work that the striatum and regions within the midbrain are highly populated with oxytocin receptors (Insel and Shapiro, 1992; King et al., 2015).”
Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain
Freeman, S. M., Palumbo, M. C., Lawrence, R. H., Smith, A. L., Goodman, M. M., & Bales, K. L. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0315-3 · Cited by 82 · see citing works
Epigenetic modification of OXT and human sociability
Haas, B. W., Filkowski, M. M., Cochran, R. N., Denison, L., Ishak, A., Nishitani, S., & Smith, A. K. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602809113 · Cited by 91 · see citing works
“Although mounting data strongly support the role of OXTR in the phenotypic expression of sociability in humans (5, 6) and animals (7), the roles of other oxytocin pathway genes has received relatively little attention.”
Background
Oxytocin receptor dynamics in the brain across development and species
Vaidyanathan, R., & Hammock, E. A. D. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22403 · Cited by 82 · see citing works
Long-term oxytocin administration enhances the experience of attachment
Bernaerts, S., Prinsen, J., Berra, E., Bosmans, G., Steyaert, J., & Alaerts, K. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.01.010 · Cited by 90 · see citing works
Oxytocin – The Sweet Hormone?
Leng, G., & Sabatier, N. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.02.007 · Cited by 89 · see citing works
The neurobiological reward system in Prolonged Grief Disorder (PGD): A systematic review
Kakarala, S. E., Roberts, K. E., Rogers, M., Coats, T., Falzarano, F., Gang, J., Chilov, M., Avery, J., Maciejewski, P. K., Lichtenthal, W. G., et al. (2020) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2020.111135 · Cited by 85 · see citing works
The Monogamy Paradox: What Do Love and Sex Have to Do With It?
Carter, C. S., & Perkeybile, A. M. (2018) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2018.00202 · Cited by 85 · see citing works
“The individual differences seen in sociality in this species have been associated with genetic variation in the Oxtr, which influences variation in receptor protein expression (King et al., 2016).”
Lost connections: Oxytocin and the neural, physiological, and behavioral consequences of disrupted relationships
Pohl, T. T., Young, L. J., & Bosch, O. J. (2019) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2017.12.011 · Cited by 83 · see citing works
Self-citation
Integrative pathways linking close family ties to health: A neurochemical perspective.
Uchino, B. N., & Way, B. M. (2017) · American Psychologist · doi:10.1037/amp0000049 · Cited by 85 · see citing works
Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia
Loth, M. K., & Donaldson, Z. R. (2020) · Endocrinology · doi:10.1210/endocr/bqaa223 · Cited by 74 · see citing works
“Finally, individual differences in OXTR levels in the NAc are also tied to variation in bond formation within male prairie voles (40).”
Background
Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: A post-mortem study
Uhrig, S., Hirth, N., Broccoli, L., von Wilmsdorff, M., Bauer, M., Sommer, C., Zink, M., Steiner, J. H., Frodl, T., Malchow, B., et al. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.04.019 · Cited by 75 · see citing works
Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders
Zhang, R., Zhang, H.-F., Han, J., & Han, S. (2017) · Neuroscience Bulletin · doi:10.1007/s12264-017-0120-7 · Cited by 76 · see citing works
“In prairie voles, one non-coding polymorphism in the Oxtr (SNP2) explains the variance in OXTR expression in particular brain regions [61].”
Background
Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects
Zhubi, A., Chen, Y., Guidotti, A., & Grayson, D. R. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.02.003 · Cited by 74 · see citing works
The Parental Brain
Numan, M. (2020) · doi:10.1093/oso/9780190848675.001.0001 · Cited by 101 · see citing works
Oxytocin and sex differences in behavior
Caldwell, H. K. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.02.002 · Cited by 64 · see citing works
Oxytocin differentially modulates specific dorsal and ventral striatal functional connections with frontal and cerebellar regions
Zhao, Z., Ma, X., Geng, Y., Zhao, W., Zhou, F., Wang, J., Markett, S. A., Biswal, B. B., Ma, Y., Kendrick, K. M., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.09.067 · Cited by 55 · see citing works
Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior
Wircer, E., Blechman, J., Borodovsky, N., Tsoory, M., Nunes, A. R., Oliveira, R. F., & Levkowitz, G. (2017) · eLife · doi:10.7554/elife.22170 · Cited by 60 · see citing works
“DOI: 10.7554/eLife.22170 1 of 25 of OXT and/or its cognate receptor are not necessarily lethal; however, they may disrupt both physi- ological and psychological responses such as stress and social behaviors (King et al., 2016; Bosch et al., 2005).”
BackgroundInfluential
Improving the precision of intranasal oxytocin research
Winterton, A., Westlye, L. T., Steen, N. E., Andreassen, O. A., & Quintana, D. S. (2020) · Nature Human Behaviour · doi:10.1038/s41562-020-00996-4 · Cited by 62 · see citing works
Oxytocin as Treatment for Social Cognition, Not There Yet
Erdozain, A. M., & Peñagarikano, O. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00930 · Cited by 61 · see citing works
“Specifically, a certain single SNP in the OXTR gene modulated OXTR expression in the nucleus accumbens, a structure widely implicated in the processing of reward, and correlated with the propensity of the animals to form social attachments (28).”
Background
The Biology of Vasopressin
Sparapani, S., Millet-Boureima, C., Oliver, J., Mu, K., Hadavi, P., Kalostian, T., Ali, N., Avelar, C. M., Bardies, M., Barrow, B., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9010089 · Cited by 63 · see citing works
The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives
Blumenthal, S. A., & Young, L. J. (2023) · Biology · doi:10.3390/biology12060844 · Cited by 59 · see citing works
“These genetic variations may also influence social behavior, as male C/C prairie voles display enhanced social attachment as compared to C/T and T/T animals [71].”
BackgroundSelf-citation
Variation, plasticity, and alternative mating tactics: Revisiting what we know about the socially monogamous prairie vole
Madrid, J. E., Parker, K. J., & Ophir, A. G. (2020) · Advances in the study of behavior · doi:10.1016/bs.asb.2020.02.001 · Cited by 55 · see citing works
“This result in males is consistent with other laboratory research showing that polymorphisms in non-coding regions in the prairie vole oxytocin gene, oxtr, predict OTR density in the NAcc and individual variation in laboratory pair bonding (King et al., 2016).”
Result
Oxytocin receptor gene polymorphisms, attachment, and PTSD: Results from the National Health and Resilience in Veterans Study
Sippel, L. M., Han, S., Watkins, L. E., Harpaz‐Rotem, I., Southwick, S. M., Krystal, J. H., Olff, M., Sherva, R., Farrer, L. A., Kranzler, H. R., et al. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.07.008 · Cited by 57 · see citing works
“Among voles, genetic variation in nonencoding regions of OXTR contribute to OXTR transcription levels, oxytocin receptor density, and individual differences in social cognition and behavior (King et al., 2016).”
Background
Circuits for social learning: a unified model and application to autism spectrum disorder
DeMayo, M. M., Young, L. J., Hickie, I. B., Song, Y. J. C., & Guastella, A. J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.034 · Cited by 52 · see citing works
“In humans, oxytocin receptors are dense within the striatum, offering a mechanism through which genetic oxytocin receptor pathways influence striatal connectivity (King et al., 2016; Loth et al., 2014).”
BackgroundSelf-citation
Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
Hernandez, L. M., Lawrence, K. E., Padgaonkar, N. T., Inada, M., Hoekstra, J. N., Lowe, J. K., Eilbott, J., Jack, A., Aylward, E., Gaab, N., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0750-9 · Cited by 54 · see citing works
Evolution of affiliation: patterns of convergence from genomes to behaviour
Fischer, E. K., Nowicki, J. P., & O’Connell, L. A. (2019) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2018.0242 · Cited by 46 · see citing works
Oxytocin‐ and arginine vasopressin‐containing fibers in the cortex of humans, chimpanzees, and rhesus macaques
Flattery, C. N. R., Ross, A. P., Sahu, S. P., Siegel, E. R., Dooyema, J. M., Cree, M. A., Stopa, E. G., Young, L. J., Rilling, J. K., Albers, H. E., et al. (2018) · American Journal of Primatology · doi:10.1002/ajp.22875 · Cited by 50 · see citing works
Self-citation
Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders
Baribeau, D. A., Dupuis, A., Paton, T., Scherer, S. W., Schachar, R. J., Arnold, P. D., Szatmári, P., Nicolson, R., Georgiades, S., Crosbie, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10821-0 · Cited by 45 · see citing works
How does oxytocin modulate human behavior?
Yao, S., & Kendrick, K. M. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02898-1 · Cited by 55 · see citing works
“Indeed, more social individuals, or those exposed to social enrichment, tend to have higher basal OT concentrations [18, 19] and receptor expression density in brain reward areas within species may also re ﬂ ect individual levels of sociality [17, 20 – 22].”
Investigation of Oxtr-expressing Neurons Projecting to Nucleus Accumbens using Oxtr-ires-Cre Knock-in prairie Voles (Microtus ochrogaster)
Horie, K., Inoue, K., Nishimori, K., & Young, L. J. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.08.023 · Cited by 46 · see citing works
“Recent research has focused on understanding how genes, neuronal modulators, receptors, and circuits regulate social bond formation and maintenance, which may have translational implications for improving quality of life in certain psychiatric disorders such as autism, PTSD, and depression (Modi et al., 2015; Arai et…”
BackgroundSelf-citation
Oxytocin receptors are widely distributed in the prairie vole (Microtus ochrogaster) brain: Relation to social behavior, genetic polymorphisms, and the dopamine system
Inoue, K., Ford, C. L., Horie, K., & Young, L. J. (2022) · Journal of Comparative Neurology · doi:10.1002/cne.25382 · Cited by 45 · see citing works
“However, no Oxtr mRNA-positive cells were detected in the SNR in voles of either genotype (Figure 7g,h), suggesting that OXTR binding in the SNR is on projections from another brain area, most likely the striatum, where Oxtr expression is genotype dependent (King et al., 2016) (Figure 7).”
BackgroundResultInfluentialSelf-citation
Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry
Ford, C. L., & Young, L. J. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.11.007 · Cited by 46 · see citing works
“In prairie voles, for instance, such sequence variation determines individual variation in striatal oxytocin receptor density [12], which predicts resiliency to early life neglect with respect to adult social bonding [14].”
BackgroundSelf-citation
Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism
Hernandez, L. M., Krasileva, K., Green, S. A., Sherman, L. E., Ponting, C., McCarron, R., Lowe, J. K., Geschwind, D. H., Bookheimer, S. Y., & Dapretto, M. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.209 · Cited by 43 · see citing works
Perinatal bisphenol A (BPA) exposure alters brain oxytocin receptor (OTR) expression in a sex- and region- specific manner: A CLARITY-BPA consortium follow-up study
Witchey, S. K., Fuchs, J., & Patisaul, H. B. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.06.007 · Cited by 40 · see citing works
“OT is synthesized primarily by the paraventricular (PVN) and supraoptic nuclei (SON) and released in multiple areas of the mesolimbic dopamine system and other brain nuclei that play a role in food intake, social recognition, mate choice, anxiety, empathy, parental care and other socioemotional behaviors (Caldwell, 20…”
Background
Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles
Borie, A. M., Agezo, S., Lunsford, P., Boender, A. J., Guo, J.-D., Zhu, H., Berman, G. J., Young, L. J., & Liu, R. C. (2022) · Current Biology · doi:10.1016/j.cub.2022.01.014 · Cited by 39 · see citing works
Self-citation
A precision medicine approach to oxytocin trials
Andari, E., Hurlemann, R., & Young, L. J. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_29 · Cited by 40 · see citing works
“Importantly, our group has recently demonstrated that the density of OTR variability between individuals within the prairie vole species in the ventral striatum is the result of gene polymorphisms in the OTR gene (King et al. 2016).”
BackgroundSelf-citation
Functional characterization of an oxytocin receptor gene variant (rs2268498) previously associated with social cognition by expression analysis in vitro and in human brain biopsy
Reuter, M., Montag, C., Altmann, S., Bendlow, F., Elger, C. E., Kirsch, P., Becker, A. J., Schoch, S., Simon, M., Weber, B., et al. (2016) · Social Neuroscience · doi:10.1080/17470919.2016.1214174 · Cited by 37 · see citing works
Brain functional networks associated with social bonding in monogamous voles
López-Gutiérrez, M. F., Gracia-Tabuenca, Z., Ortiz, J. J., Camacho, F., Young, L. J., Paredes, R. G., Díaz, N. F., Portillo, W., & Alcauter, S. (2021) · eLife · doi:10.7554/elife.55081 · Cited by 40 · see citing works
“Variation in OXT receptor density in the NAcc relates to partner preference in prairie voles (King et al., 2016).”
BackgroundSelf-citation
Comparative role of reward in long-term peer and mate relationships in voles
Goodwin, N. L., Lopez, S., Lee, N. S., & Beery, A. K. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2018.10.012 · Cited by 34 · see citing works
“Because of these selective social relationships, prairie voles have been hailed as an emerging model organism for the translational study of human social deficits in disorders such as autism spectrum disorder and schizophrenia (King et al., 2016; Lim et al., 2005; McGraw and Young, 2010; Modi and Young, 2012; Sadino a…”
Method
Oxytocin, vasopressin and social behavior in the age of genome editing: a comparative perspective
Boender, A. J., & Young, L. J. (2020) · Hormones and Behavior · doi:10.1016/j.yhbeh.2020.104780 · Cited by 30 · see citing works
Self-citation
Distribution of brain oxytocin and vasopressin V1a receptors in chimpanzees (Pan troglodytes): comparison with humans and other primate species
Rogers Flattery, C. N., Coppeto, D. J., Inoue, K., Rilling, J. K., Preuss, T. M., & Young, L. J. (2022) · Brain Structure and Function · doi:10.1007/s00429-021-02369-7 · Cited by 31 · see citing works
Self-citation
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Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles
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Oxytocin receptor binding in the titi monkey hippocampal formation is associated with parental status and partner affiliation
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“Variations in the Oxtr gene are associated with social recognition (Skuse et al., 2014), attachment and pair-bonding affiliative behavior (Walum et al., 2012; King et al., 2016), empathy (Rodrigues et al., 2009), and social interactions (Murakami et al., 2011) in humans and animal models.”
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Self-citation

Authors: King, L. B., Walum, H., Inoue, K., Eyrich, N. W., & Young, L. J.
Affiliations: Emory University (US)
Corresponding author: Young, Larry J.
ORCID: King, Lanikea B.
Inoue, Kiyoshi
Eyrich, Nicholas W.
Young, Larry J.
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2016-07
Volume: 80
Issue: 2
Pages: 160-169
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2015.12.008
PMC: PMC4909578
OpenAlex: W2216755319
Semantic Scholar: 01a573b667c990664ff2f484a535ecfac25237b4
Cited by: 191
References: 86
Citations by year: 2026: 6 · 2025: 14 · 2024: 16 · 2023: 11 · 2022: 18 · 2021: 24 · 2020: 32 · 2019: 10 · 2018: 18 · 2017: 21 · 2016: 19 · 2015: 2
FWCI: 32.71
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (R01MH096983, 1P50MH100023, 5T32GM008605, 5T32DA015040)
National Institutes of Health Office of Research Infrastructure Programs/OD (P51OD11132)
Topics: Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: oxytocin receptor gene, oxytocin receptor, Microtus ochrogaster, social attachment, brain region-specific gene expression, allelic imbalance, cis-regulatory elements, intronic polymorphism, nucleus accumbens, striatum, mate preferences, monogamy, genetic regulation of gene expression, autism spectrum disorder
MeSH terms: Autism Spectrum Disorder, Alleles, Animals, Behavior, Animal, Arvicolinae, Individuality, Nucleus Accumbens, Object Attachment, Polymorphism, Genetic, RNA, Messenger, Social Behavior, Sequence Analysis, DNA, Receptors, Oxytocin

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Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment

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