Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“Despite a widely varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“Similarly, although genome-wide copy number variation analyses have not highlighted OXTR (Glessner et al. 2009), a recent report described deletion of the region including OXTR, CAV3, and three neighboring genes in a single proband in one of 119 families (Gregory et al.”

“…enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastella et al. 2008b; Hurlemann et al. 2010).”

“OXT facilitates social recognition behavior (Ferguson et al. 2000) and modulates maternal behavior (Pedersen and Prange 1979; Kendrick et al.”

“1 (Wang et al. 2009), 5p15 (Weiss et al.”

“Intravenous or intranasal applications of OXT in youth (Guastella et al. 2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“…enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastella et al. 2008b; Hurlemann et al. 2010).”

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“Analysis of association with ASD diagnosis Family-based single marker and haplotype association analyses were performed using the family-based association test (FBAT; (Horvath et al. 2001)) and haplotype-based association test (HBAT; (Horvath et al. 2004); FBAT version 1.7.2).”

“Reported reductions in plasma OXT (Green et al. 2001; Modahl et al. 1998) and increases in unprocessed OXT peptides (Green et al.”

“2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“2010) and adult (Hollander et al. 2007; Hollander et al. 2003; Andari et al. 2010) cohorts with ASD generally improved various functions relevant to social behavior.”

“However, genetic linkage studies have indicated signals for linkage on nearly every chromosome (International Molecular Genetic Study of Autism Consortium 1998; Philippe et al. 1999; Barrett et al. 1999; Risch et al. 1999; International Molecular Genetic Study of Autism Consortium 2001; Yonan et al. 2003; Ylisaukko-oj…”

“2009), 5p15 (Weiss et al. 2009), and 20p13 (Anney et al.”

“Wang et al. (2009) described association of OXTR marker rs75775 (P=0.003) and Anney et al. (2010) described association of OXTR marker rs2301261 (P= 0.016).”

“FBAT analysis was performed with both the additive model and the recessive model because significant association has been reported with each model (Wu et al. 2005; Yrigollen et al. 2008).”

“Despite a widely varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“Moreover, OXT signaling facilitates social preferences between adult monogamous rodents (Williams et al. 1992; Williams et al. 1994).”

“Most genome-wide linkage analyses did not find a peak near the OXTR gene on chromosome 3p25 (International Molecular Genetic Study of Autism Consortium 1998; Philippe et al. 1999; Barrett et al. 1999; Risch et al. 1999; International Molecular Genetic Study of Autism Consortium 2001).”

“…varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“In Caucasian families, the opposite allele, the rs2254298 G allele, was associated with ASD risk in one study (Jacob et al. 2007) and contributed to a risk haplotype in another study (Lerer et al. 2008).”

“Reported reductions in plasma OXT (Green et al. 2001; Modahl et al. 1998) and increases in unprocessed OXT peptides (Green et al. 2001) in young children with ASD are contrasted by measures of higher baseline levels of serum OXT in young adults with ASD compared to control subjects (Jansen et al.…”

“In humans, there have been a number of recent studies demonstrating enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastell…”

“In-house SNP genotyping and quality control Genotyping was performed using TaqMan™ SNP genotyping assays on the ABI Prism 7900HT and analyzed with SDS software as previously described (Campbell et al. 2006; Campbell et al. 2008).”

“…varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“Analysis of association with ASD diagnosis Family-based single marker and haplotype association analyses were performed using the family-based association test (FBAT; (Horvath et al. 2001)) and haplotype-based association test (HBAT; (Horvath et al. 2004); FBAT version 1.7.2).”

“Despite a widely varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“2000) and modulates maternal behavior (Pedersen and Prange 1979; Kendrick et al. 1987).”

“…enhanced functions relevant to social behavior following oxytocin application in healthy adults (Heinrichs et al. 2003; Kosfeld et al. 2005; Rimmele et al. 2009; Zak et al. 2007; Domes et al. 2007a; Domes et al. 2007b; Guastella et al. 2008a; Guastella et al. 2008b; Hurlemann et al. 2010).”

“Further, in those studies that included analysis of phenotype data, the OXTR markers associated with ASD failed to show association with measures of social behavior in individuals with ASD (Lerer et al. 2008; Yrigollen et al. 2008).”

“While different reports indicate positive association of OXTR markers in intron 3 and the 3′ UTR, the studies involved small family cohorts of less than 500 families each, increasing the risk for spurious associations (Sullivan 2007).”

“…Molecular Genetic Study of Autism Consortium 1998; Philippe et al. 1999; Barrett et al. 1999; Risch et al. 1999; International Molecular Genetic Study of Autism Consortium 2001; Yonan et al. 2003; Ylisaukko-oja et al. 2006), suggesting that multiple genes contribute to ASD susceptibility.”

“that correlate with this risk gene (Sullivan 2007; Lucht et al. 2009).”

“The gene encoding the oxytocin receptor, OXTR, is a strong functional ASD candidate gene based on its known role in modulating social behavior (Ebstein et al. 2009; Hammock and Levitt 2006).”

“Three family-based studies failed to find association of rs2254298 (Liu et al. 2010; Lerer et al. 2008; Wermter et al. 2010) and another study did not find association of rs53576 (Jacob et al.”

“…reductions in plasma OXT (Green et al. 2001; Modahl et al. 1998) and increases in unprocessed OXT peptides (Green et al. 2001) in young children with ASD are contrasted by measures of higher baseline levels of serum OXT in young adults with ASD compared to control subjects (Jansen et al. 2006).”

“Further, in those studies that included analysis of phenotype data, the OXTR markers associated with ASD failed to show association with measures of social behavior in individuals with ASD (Lerer et al. 2008; Yrigollen et al. 2008).”

“In-house SNP genotyping and quality control Genotyping was performed using TaqMan™ SNP genotyping assays on the ABI Prism 7900HT and analyzed with SDS software as previously described (Campbell et al. 2006; Campbell et al. 2008).”

“Moreover, OXT signaling facilitates social preferences between adult monogamous rodents (Williams et al. 1992; Williams et al. 1994).”

“However, genetic linkage studies have indicated signals for linkage on nearly every chromosome (International Molecular Genetic Study of Autism Consortium 1998; Philippe et al. 1999; Barrett et al. 1999; Risch et al. 1999; International Molecular Genetic Study of Autism Consortium 2001; Yonan et al. 2003; Ylisaukko-oj…”

“One possible explanation for this broad association may lie in the robust developmental expression of OXTR in many more brain areas than in the adult (Shapiro and Insel 1989; Snijdewint et al. 1989; Wang et al. 1997).”

“Also listed is whether the marker was genotyped by the Levitt lab in-house using Taqman assays or by the Broad Institute using the Affymetrix 5.0 GWAS platform both parent and teacher scales, the SRS T scores were averaged from all available informants (Constantino et al. 2009).”

“…varying clinical presentation, ASD is highly heritable, with studies demonstrating a concordance rate of 80–95% in monozygotic twins and 0–31% in dizygotic twins (Folstein and Rutter 1977; Ritvo et al. 1985; Bailey et al. 1995; Le Couteur et al. 1996; Taniai et al. 2008; Rosenberg et al. 2009).”

“We performed PCA of the AGRE ADI-R scores (Campbell et al. 2010) and obtained factor structures that were indistinguishable from those previously reported (Frazier et al. 2008); therefore, we also report association analysis of two-factor scores on the ADI-R.”

“Lerer et al. (2008) described association of the 3′ UTR marker rs1042778 G allele and Tansey et al. (2010) found association of the intergenic marker rs7632287 with ASD risk.”

“We performed PCA of the AGRE ADI-R scores (Campbell et al. 2010) and obtained factor structures that were indistinguishable from those previously reported (Frazier et al. 2008); therefore, we also report association analysis of two-factor scores on the ADI-R.”

“The gene encoding the oxytocin receptor, OXTR, is a strong functional ASD candidate gene based on its known role in modulating social behavior (Ebstein et al. 2009; Hammock and Levitt 2006).”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“…and alterations in: the gene that encodes the oxytocin receptor, OXTR, (Ebstein et al., 2009; Hammock and Levitt, 2006), in oxytocin receptors (Campbell et al., 2011; Liu et al., 2010; Skuse et al., 2014; Wermter et al., 2010; Wu et al., 2005), and in epigenetic mechanisms (Gregory et al.,…”