Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism

Abstract

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V 1a receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5′ flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5′ flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5′ flanking region and the coding region and identified 10 single nucleotide polymorphisms.

Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills

“…The present study confirms and extends two previous investigations 6,7 showing association between the AVPR1a gene and autism. Kim et al 6 observed transmission disequilibrium between the RS1 and 115 autism trios and not with the second promoter region microsatellite RS3.…”

“…For RS1, nine alleles (308-340) were identified and the distribution of allele frequencies is similar to previous reports. 6,7 For RS3, 16 alleles (318-350 bp) were identified and the distribution of allele frequencies is similar to a previous report. 5 …”

“…3 Intriguingly, in humans, similar repetitive regions have been identified in the promoter region (RS1 and RS3) as well as in the single intron (AVR), although the role of these repeat regions in receptor expression remains to be elucidated. 4,5 Recently, two independent reports demonstrated provisional association between microsatellites (RS1, RS3) in the promoter region of AVPR1a and autistic disorder 6,7 and we observed association between these microsatellites and social behavior in a nonclinical population of university students. 8 These first studies are of special interest because social communication and social interaction are among the core deficits of autistic disorder.…”

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

“…Additionally, SNPs associated with ASD are also associated with amygdala volume [29], depression/anxiety [29], negative emotionality [30], attention deficit [31], adult attachment styles [32,33] (but see [34]), affectivity, emotional loneliness and IQ [35], empathy and stress reactivity [36], observed parenting [37], with sexual phenotypes [38] and in our own studies with prosocial behavior [39]. Interestingly, the AVPR1a receptor of the closely related nonapeptide vasopressin has also been associated with ASD [40][41][42]. This provisional role of OT in ASD, is further supported by two linkage studies [43,44], clinical evidence by several groups demonstrating clinical improvement in ASD following OT administration [45][46][47][48][49][50][51] (also see [52,53]) and studies showing that ASD is also associated with alterations in OT plasma levels [54].…”

Profound Impairment in Social Recognition and Reduction in Anxiety-Like Behavior in Vasopressin V1a Receptor Knockout Mice

“…Our results support previous reports of the importance of the AVP system in these behaviors and may have clinical relevance to the understanding and treatment of similar corresponding disorders in humans. Autism, with its hallmark disturbances in social behavior, has been associated with polymorphisms in the V1aR gene (Kim et al, 2002), suggesting that modulation of this receptor and the AVP system may provide novel therapeutic targets for psychiatric disorders associated with social impairment, such as autism, as well as affective disorders such as anxiety disorder. However, the therapeutic potential of AVP treatment must not be overstated.…”