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Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment
Open accessAbstract
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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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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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“In all of our relatively small samples, NT213739 was strongly associated with NAcc expression (all P-values<4×10−10).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
What the sources say
- Not checked yetcites [58] Mouse, 2012, An encyclopedia of mouse DNA elements (Mouse ENCODE), Genome Biol source
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“Our analysis revealed two factors together explaining the majority of variance (58%).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“Only one SNP overlapped with strong signatures of transcriptional function, a SNP occurring at nucleotide 213739 (NT213739, minor allele frequency: 0.32) (Figure 3b).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“Furthermore, OXTR binding density appeared to be correlated with Oxtr mRNA levels based on in situ hybridization signal (Figure 1a).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
What the sources say
- Not checked yetcites [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 yetcites [61] Liu, 2015, Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals, Human Genome Variation source
- Not checked yetcites [62] Young, 1996, Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences, J Neuroendocrinol source
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“Clearly, as can be seen in Figure 3a many of the SNPs in our set were strongly associated with NAcc OXTR density.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“We found that NT213739 is also significantly associated with Oxtr mRNA levels in the NAcc (Figure 4b)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“and that mRNA levels and OXTR density were significantly correlated (Figure 4c, 4d).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“Exploratory factor analysis identified a cluster of striatal-olfactory regions with correlated OXTR density.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“Our data suggests that NT213739, or any of the SNPs in perfect LD with it, explain 74% of the variation in NAcc OXTR.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“OXTR signaling in the NAcc is required for mating-induced partner preference formation, a laboratory proxy of pair bonding (6).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites (A.C. Keebaugh and LJY, unpublished data)
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“OXTR density is much higher in the NAcc of prairie voles than promiscuous vole species”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
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“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)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
- Not checked yetcites [8] Johnson, 2015, Neural networks involved in social attachment and pair bonding, Curr Opin Behav Sci source
- Not checked yetcites [34] Young, 2001, Cellular mechanisms of social attachment, Horm Behav source
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In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [41] Wittkopp, 2012, Cis-regulatory elements: Molecular mechanisms and evolutionary processes underlying divergence, Nat Rev Genet source
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“Variation in NAcc OXTR density is correlated with individual differences in monogamy-related behavior in males in naturalistic settings (40).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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
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“OXTR density also varies between individual prairie voles, especially in the NAcc along with the CP (36).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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
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In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
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In the paper
“These data strongly suggest that cis-REs linked to NT204321 generate individual variation in expression of Oxtr in select brain tissues.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
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“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“In a key region of the MLR, the NAcc, OXTR activation is necessary for prairie vole partner preference formation (35)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
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“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
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In the paper
“and OXTR variation mediates individual differences in pair bonding behaviors (37–39).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [39] Ophir, 2012, Oxytocin receptor density is associated with male mating tactics and social monogamy, Horm Behav source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In some rodent brain regions, OXTR expression is regulated by gonadal steroids in a species specific manner.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [68] Bale, 1995, Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites, Endocrinology source
- Not checked yetcites [69] Odom, 2007, Tissue-specific transcriptional regulation has diverged significantly between human and mouse, Nat Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus direct measures of brain phenotype are likely to yield stronger effect sizes than reported in behavioral studies.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [80] Tost, 2011, Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults, Biol Psychiatry source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent meta-analysis supports the conclusion that genetic variation in OXTR is associated with ASD diagnosis (21)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [21] LoParo, 2015, The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis, Mol Psychiatry source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Here, we confirm a genetic role for naturally occurring OXTR density differences that contribute to individual variation in social behavior (36, 40).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results highlight a potentially conserved role for OXTR in social cognition between species despite likely differences in sites of expression.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to region-specific effects, OXTR signaling enhances functional connectivity within a network of regions during prairie vole pair bond formation (79).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 23
- Probably not a substantial claim. 19
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plaincorrelationaln = 85- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
boostedcorrelationaln = 2- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
boostedcorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Allelic imbalance is strongest in the striatum and genotype-OXTR associations are most robust in this region.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [19] Walum, 2012, Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior, Biol Psychiatry source
- Not checked yetcites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“OXTR is distributed throughout the brain of many vertebrates and, importantly, the pattern of OXTR distribution is diverse between species (32, 33).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
- Not checked yetcites [33] Freeman, 2014, The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta), Psychoneuroendocrinology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some individuals have heterogeneous responses to OXT (22, 23), which may involve interaction with OXTR genetic polymorphisms (24–27).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [22] Bartz, 2011, Social effects of oxytocin in humans: Context and person matter, Trends Cogn Sci
- Not checked yetcites [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 yetcites [24] Marsh, 2012, The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype, Psychopharmacology source
- Not checked yetcites [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 yetcites [26] Chen, 2015, Genetic modulation of oxytocin sensitivity: A pharmacogenetic approach, Transl Psychiatry source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [1] Rilling, 2014, The biology of mammalian parenting and its effect on offspring social development, Science source
- Not checked yetcites [2] Numan, 2016, Neural mechanisms of mother-infant bonding and pair bonding: Similarities, differences, and broader implications, Horm Behav source
- Not checked yetcites [3] Dolen, 2013, Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin, Nature source
- Not checked yetcites [4] Goodson, 2009, Mesotocin and nonapeptide receptors promote estrildid flocking behavior, Science source
- Not checked yetcites [6] Young, 2004, The neurobiology of pair bonding, Nat Neurosci source
- Not checked yetcites [7] Goodson, 2012, Evolving nonapeptide mechanisms of gregariousness and social diversity in birds, Horm Behav source
- Not checked yetcites [8] Johnson, 2015, Neural networks involved in social attachment and pair bonding, Curr Opin Behav Sci source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28–31).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [28] Loth, 2014, Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events, Biol Psychiatry source
- Not checked yetcites [29] Lucas-Thompson, 2013, Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress, Horm Behav source
- Not checked yetcites [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 yetcites [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
plainconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Allelic imbalance is commonly observed in a tissue-specific manner (51, 52).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [48] Johnson, 2005, Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics, Pharmacol Ther source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42–46).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > INTRODUCTION
What the sources say
- Not checked yetcites [32] Donaldson, 2008, Oxytocin, vasopressin, and the neurogenetics of sociality, Science source
- Not checked yetcites [42] Bendesky, 2011, Genetic contributions to behavioural diversity at the gene-environment interface, Nat Rev Genet source
- Not checked yetcites [43] Linnen, 2013, Adaptive evolution of multiple traits through multiple mutations at a single gene, Science source
- Not checked yetcites [44] Oleksiak, 2002, Variation in gene expression within and among natural populations, Nat Genet source
- Not checked yetcites [45] Cretekos, 2008, Regulatory divergence modifies limb length between mammals, Genes Dev source
- Not checked yetcites [46] Hammock, 2005, Microsatellite instability generates diversity in brain and sociobehavioral traits, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Comparisons of ~1500 bp of 5’ flanking regions from the Oxtr gene reveal only a few SNPs and 99% homology between the species (63).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Polymorphic cis-REs have been shown to influence CTCF binding (71, 72) and DNA looping (73).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [73] Dekker, 2013, Exploring the three-dimensional organization of genomes: Interpreting chromatin interaction data, Nat Rev Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“and accumulates rare SNPs in cases of ASD (62).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [62] Young, 1996, Species differences in central oxytocin receptor gene expression: Comparative analysis of promoter sequences, J Neuroendocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together these data suggest that NT213739 is strongly associated with transcriptional variation of the Oxtr gene and tightly linked to a cis-RE.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > RESULTS
hedgedcorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Interestingly, DNA methylation of OXTR in humans may be mediated by an intronic SNP (67).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [67] Insel, 1993, Gonadal steroids have paradoxical effects on brain oxytocin receptors, J Neuroendocrinol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this manner cis-REs appear to contribute exquisite control over OXTR and through this process, influence behavioral diversity in prairie voles.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [75] Russo, 2013, The brain reward circuitry in mood disorders, Nat Rev Neurosci source
- Not checked yetcites [76] Luscher, 2011, Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling, Neuron source
- Not checked yetcites [77] Abi-Dargham, 2014, Schizophrenia: Overview and dopamine dysfunction, J Clin Psychiatry source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Additionally, the human intron may contain other cis-REs (61)”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [61] Liu, 2015, Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals, Human Genome Variation source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Discussion · boosted
In the paper
“We note that such comparisons should be made with the understanding that transcription factor binding sites may differ between species (70).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [21] LoParo, 2015, The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis, Mol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (68, 69).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [68] Bale, 1995, Regulation of oxytocin receptor messenger ribonucleic acid in the ventromedial hypothalamus by testosterone and its metabolites, Endocrinology source
- Not checked yetcites [69] Odom, 2007, Tissue-specific transcriptional regulation has diverged significantly between human and mouse, Nat Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > MATERIALS AND METHODS > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“DNA methylation of Oxtr differs between brain regions in rodents (65, 66).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [65] Beery, 2016, Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats, Horm Behav source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Associations between genetic information and brain data were examined using linear regression with Bonferroni corrections for multiple comparisons.”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > MATERIALS AND METHODS > Statistical analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“and others have reported associations with endophenotypes of ASD (20, 82, 83), including structural variability in brain regions relevant to social cognition (80, 84).”
§ Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [83] Inoue, 2010, Association between the oxytocin receptor gene and amygdalar volume in healthy adults, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
Citations
Cites
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
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
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“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 16,450
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×
“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×
“The OXTR is distributed throughout the brain of many vertebrates, and the pattern of OXTR distribution is diverse among species (32,33).”
Self-citationSocial 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 1,581 · cited 1×
“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×
“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×
“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
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×
“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).”
Cited by
Sorted by citations
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 480
“For example, there is robust individual genetically determined variation in oxytocin receptor density in prairie vole nucleus accumbens (King et al. 2016).”
BackgroundSelf-citationIs 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
“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.”
BackgroundThe 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
Self-citationJohnson, Z. V., & Young, L. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.034 · Cited by 242
“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-citationFreeman, S. M., & Young, L. J. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12382 · Cited by 196
“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
Metadata
- Authors
- King, L. B., Walum, H., Inoue, K., Eyrich, N. W., & Young, L. J.
- Affiliations
- Emory University (US)
- Corresponding author
- Young, Larry J.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 80
- Issue
- 2
- Pages
- 160-169
- ISSN
- 0006-3223 (ISSN-L)
- 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
- FWCI
- 32.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › 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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