Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition

Abstract

Evidence both from animal and human studies suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are likely candidates to confer risk for autism spectrum disorders (ASD). In lower mammals, oxytocin is important in a wide range of social behaviors, and recent human studies have shown that administration of oxytocin modulates behavior in both clinical and non-clinical groups. Additionally, two linkage studies and two recent association investigations also underscore a possible role for the OXTR gene in predisposing to ASD. We undertook a comprehensive study of all 18 tagged SNPs across the entire OXTR gene region identified using HapMap data and the Haploview algorithm. Altogether 152 subjects diagnosed with ASDs (that is, DSM IV autistic disorder or pervasive developmental disorder-NOS) from 133 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED set of programs. Significant association with single SNPs and haplotypes (global P-values < 0.05, following permutation test adjustment) were observed with ASD. Association was also observed with IQ and the Vineland Adaptive Behavior Scales (VABS). In particular, a five-locus haplotype block (rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated with ASD (nominal global P = 0.000019; adjusted global P = 0.009) and a single haplotype (carried by 7% of the population) within that block showed highly significant association (P = 0.00005). This is the third association study, in a third ethnic group, showing that SNPs and haplotypes in the OXTR gene confer risk for ASD. The current investigation also shows association with IQ and total VABS scores (as well as the communication, daily living skills and socialization subdomains), suggesting that this gene shapes both cognition and daily living skills that may cross diagnostic boundaries.

Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population

“…These results may suggest the potential role of OXTR in ASD, as implicated in the previous studies. [20][21][22] In contrast to the case-control analysis, we did not obtain a support for the association in the family-based analysis. This could be due to the insufficient power with limited numbers of informative families.…”

“…They investigated four SNPs in Han-Chinese ASD trios and found that 'A' alleles of rs53576 and rs2254298 were significantly overtransmitted. Two Caucasian studies 21,22 also found the association between OXTR and ASD, but the detail of the results was inconsistent compared with the Chinese result. Jacob et al 21 investigated the two SNPs (rs53576 and rs2254298), which were suggested in the Chinese study, and found that the 'A' allele of rs2254298 was undertransmitted, not overtransmitted.…”

“…These were reported to be associated with ASD in the previous studies. [20][21][22][23] Thus, a total of 12 SNPs were selected. All SNPs were genotyped by using TaqMan genotyping platform.…”

“…To date, Chinese and Caucasian studies observed significant genetic associations between OXTR and ASD. [20][21][22] Among them, Wu et al 20 were the first to study the genetic association of single-nucleotide polymorphisms (SNPs) of OXTR in autism. They investigated four SNPs in Han-Chinese ASD trios and found that 'A' alleles of rs53576 and rs2254298 were significantly overtransmitted.…”

“…No association of rs53576 was observed. Lerer et al 22 found an association of a haplotype comprising rs22254298 and four other SNPs (rs237897-rs13316193-rs237889-rs2254298-rs2268494) with ASD, but as a single SNP, rs2254298 was not associated with ASD (Lerer et al 22 ). Yrigollen et al 23 found that rs2268490, which was in the same haploblock of rs2254298, was associated with ASD.…”