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

Daniel B Campbell,Elizabeth A D Hammock,Shaine T Jones,Dibyadeep Datta,Evon Batey Lee,Pat Levitt,James S Sutcliffe

doi:10.1007/s11689-010-9071-2

Abstract

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Highlights

Autism spectrum disorder (ASD) is characterized by abnormalities in three domains: social interaction deficits,J Neurodevelop Disord (2011) 3:101–112 language impairments, and repetitive behaviors with restricted interests
In addition to analysis of association with ASD diagnosis, we examined association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and the Social Responsiveness Scale (SRS)
We identified 975 individuals from 618 independent families with narrow autism, defined by clinical diagnosis confirmed by both ADI-R and ADOS classification

Summary

Introduction

Autism spectrum disorder (ASD) is characterized by abnormalities in three domains: social interaction deficits,J Neurodevelop Disord (2011) 3:101–112 language impairments, and repetitive behaviors with restricted interests. 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; Guastella et al 2008b; Hurlemann et al 2010). 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

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