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

Joe A. Hettinger, Physiology, Queen's University, 191 Portsmouth Avenue, Kingston, ON K7M 8A6, Canada, Xudong Liu, PhD, Psychiatry, Queen's University, 191 Portsmouth Ave, Kingston, ON K7M 8A6, Canada, Melissa Hudson, Psychiatry, Queen's Univerity, 191 Portsmouth Ave, Kingston, ON K7M 8A6, Canada, Ron C. Michaelis, Biology, Western Carolina University, Cullowhee, NC, Charles E. Schwartz, Center for Molecular Studies, Greenwood Genetic Center, Greenwood, SC, M.E. Suzanne Lewis, MD, University of British Columbia, C234-4500 Oak Street, Vancouver, BC V6H 3N1, Canada, and Jeanette J.A. Holden, PhD, Psychiatry & Physiology, Queen's University, 191 Portsmouth Ave, Kingston, ON K7M 8A6, Canada.

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 Mr 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.


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