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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
Overview
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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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40 Not checked yet · 26 Own result · 8 Own interpretation · 4 Own method · 1 Supported so far · 1 Partly supported · 1 No basis given · accuracy not yet measured
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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
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In the paper
“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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In the paper
“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
plainn = 85- Asserted: passes — The authors put it forward as true.
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In the paper
“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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In the paper
“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 the paper
“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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In the paper
“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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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
plaincorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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In the paper
“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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In the paper
“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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- Probably not a substantial claim. 19
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The cited sources support only part of this claim — read each source’s verdict below.
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
- Partly supportedcites [33] Freeman, 2014, The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta), Psychoneuroendocrinology sourceExperimental — accuracy not yet measured
The Discussion (Comparison to OXTR expression in other primate species; page not provided) describes distinct OXTR distributions among primates and rodents, supporting the species-difference claim. The Results (In situ hybridization confirms OXTR expression; page not provided) detect a consistent signal in only five macaque brain areas, so the paper does not establish that OXTR is distributed throughout the brain of many vertebrates. (LLM, conf=0.84)
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.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated 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
- Supportedcites [43] Linnen, 2013, Adaptive evolution of multiple traits through multiple mutations at a single gene, Science source
The passage on Agouti promoters (section labeled Abstract; page unavailable) links promoter regions to adaptive coat-color traits in Sand Hills mice. It concludes that cis-regulatory changes are among the mechanisms involved in their color adaptation, supporting the cited statement as a general example. (LLM, conf=0.88)
- Not checked yetcites [44] Oleksiak, 2002, Variation in gene expression within and among natural populations, Nat Genet source
- Supportedcites [45] Cretekos, 2008, Regulatory divergence modifies limb length between mammals, Genes Dev source
The Abstract reports that replacing a mouse limb enhancer with a bat enhancer increased Prx1 expression and produced significantly longer forelimbs. It concludes that changes in noncoding regulatory sequences can contribute to evolutionary morphological differences. (LLM, conf=0.94)
- 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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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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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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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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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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
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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
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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
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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
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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.
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Probably not a substantial claim. It may state two separate claims as one.
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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.
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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
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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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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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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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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.
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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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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.
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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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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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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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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.
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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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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.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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.
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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.
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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.
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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
“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.
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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
“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.
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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. 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.
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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
“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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
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“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×
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Numan, M., & Young, L. J. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.015 · Cited by 355 · cited 2×
“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-citationLerer, 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×
“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).”
InfluentialStatistical 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 347 · cited 1×
“Individual reports of the effects of intranasal OXT should be interpreted cautiously (11).”
Self-citationThe 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×
“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).”
InfluentialRoss, 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×
“OXTR autoradiography was performed as previously reported (36).”
Self-citationVerlaan, 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×
“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×
“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 276 · cited 1×
“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×
“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×
“Variation in gene expression mediated by cis-REs plays an important role in evolutionary phenotypic change (32, 42-46).”
Olazábal, D. E., & Young, L. J. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2005.12.010 · Cited by 230 · cited 2×
“The OXTR density also varies among individual prairie voles, especially in the NAc and the CP (35).”
Self-citationThe 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×
“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Self-citationParker, 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×
“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).”
InfluentialVariation 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×
“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-citationThompson, 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×
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
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×
“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-citationYoung, L. J., & Barrett, C. E. (2015) · Science · doi:10.1126/science.aaa8120 · Cited by 200
Self-citationJohnson, 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×
“In addition to region-specific effects, OXTR signaling enhances functional connectivity within a network of regions during prairie vole pair bond formation (78).”
Self-citationFreeman, 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×
“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
Self-citationAssociation 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×
“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×
“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 159 · cited 1×
“Allelic imbalance is commonly observed in a tissue-specific manner (50,51).”
Keebaugh, A. C., & Young, L. J. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.07.018 · Cited by 154 · cited 2×
“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).”
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×
“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-citationEvolving 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×
“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×
“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).”
Barrett, C. E., Arambula, S. E., & Young, L. J. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.73 · Cited by 115 · cited 1×
“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-citationGonadal 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×
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (67,68).”
Self-citationYoung, 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×
“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-citationGenetic 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×
“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×
“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).”
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
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 88 · cited 1×
“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).”
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
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×
“DNA methylation of OXTR in humans may be mediated by an intronic SNP (66).”
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 82 · cited 1×
“The partner preference was performed as previously described (55).”
Self-citationModi, 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
Self-citationBeery, 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×
“DNA methylation of Oxtr differs between brain regions in rodents (64,65).”
Mizumoto, Y., Kimura, T., & Ivell, R. (1997) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(97)00195-0 · Cited by 79 · cited 2×
“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).”
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×
“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).”
Bale, T. L., & Dorsa, D. M. (1995) · Endocrinology · doi:10.1210/endo.136.11.7588251 · Cited by 65 · cited 1×
“For example, testosterone increases OXTR in the hypothalamus of rats but decreases OXTR in mice (68, 69).”
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×
“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×
“It has been proposed that OXT influences these complex social behaviors by increasing the salience and reinforcing value of social stimuli (9).”
Self-citationHarony-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×
“DNA methylation of Oxtr differs between brain regions in rodents (64,65).”
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×
“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×
“Sense and antisense (35)S-UTP–labeled RNA probes for prairie vole Oxtr mRNA were generated as described previously (54).”
Self-citationGenetic 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
Visser, M., Palstra, R.-J., & Kayser, M. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv029 · Cited by 57 · cited 1×
“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×
“Allelic imbalance is commonly observed in a tissue-specific manner (51, 52).”
Donaldson, Z. R., & Young, L. J. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003729 · Cited by 52 · cited 1×
“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).”
Lucas-Thompson, R. G., & Holman, E. A. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.02.015 · Cited by 51 · cited 1×
“Early life stress in humans can interact with OXTR variation to influence adult social behavior and emotional regulation (28-31).”
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
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×
“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-citationNovel 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×
“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).”
InfluentialBAC-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×
“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-citationParedes, 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×
“Polymorphic cis-REs have been shown to influence CTCF binding (70,71) and DNA looping (72).”
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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