A PPP1R1B Polymorphism is Associated with Risk for Autism Spectrum Disorders in Male-only Affected Sib-pair Families

Background:   Dopamine (DA) modulates learning, executive functions, emotional processing and social cognition, all of which are impaired in individuals with autism spectrum disorders (ASDs).  The dopamine- and cAMP-regulated phosphoprotein M_r 32kDa (DARPP-32) is encoded by the PPP1R1B gene, which is located at chromosome 17q12, and is expressed in dopaminoceptive (DAceptive) neurons.  DARPP-32 is differentially phosphorylated or dephosphorylated by D1-like or D2-like dopamine receptors with the phosphorylated state of the protein determining the downstream physiological effects of DA receptor activation.

Objectives:   To determine whether the PPP1R1B gene is associated with susceptibility to ASDs.

Methods:   Because our previous findings in DA-related genes (DRD1 and DRD2) suggested that the dopaminergic system may be affected in families with only affected males , we examined 3 polymorphisms (rs1495099G/C, rs907094T/C and rs3764352A/G) in the PPP1R1B gene in 112 male-only affected sib-pair families and a comparison group of 443 males and females.  We performed single marker and haplotype case-control comparisons as well as family-based tests including quantitative transmission disequilibrium tests (QTDT).

Results:   There was an increased frequency of rs1495099 C alleles (P=0.001) and CC genotypes (P=0.001) in affected males compared to our comparison group.  Family-based tests performed under a recessive model showed over-transmission of the C allele (P=0.0009). QTDT analyses showed associations between rs1495099 C and more severe problems with social interaction (P=0.0016) and nonverbal communication (P=0.0046), as well as increased stereotypic behaviours (P=0.0072) as determined using Autism Diagnostic Interview-Revised subdomain scores.

Conclusions:   Our findings support a role for the PPP1R1B gene in conferring risk for autism in families with only affected males and suggest that the rs1495099 C allele, or functional variants in linkage disequilibrium with this polymorphism, cause changes either in PPP1R1B expression or DARPP-32 function in DAceptive neurons in brain regions which have a role in social interaction, communication and the pathophysiology of stereotypies.