Open Access Research

DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families

Joe A Hettinger1, Xudong Liu23, Melissa L Hudson234, Alana Lee234, Ira L Cohen45, Ron C Michaelis6, Charles E Schwartz7, Suzanne ME Lewis489 and Jeanette JA Holden11011234*

Author Affiliations

1 Department of Physiology, Queen’s University, Kingston, ON, Canada

2 Queen’s Genetics and Genomics Lab at Ongwanada, Ongwanada Resource Centre, Kingston, ON, Canada

3 Department of Psychiatry, Queen’s University, Kingston, ON, Canada

4 Autism Spectrum Disorders – Canadian-American Research Consortium, Kingston, ON, Canada

5 Department of Psychology and George A. Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

6 Department of Biology, Western Carolina University, Cullowhee, North Carolina, USA

7 Center for Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina, USA

8 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

9 B.C. Child and Family Research Institute, Vancouver, BC, Canada

10 Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada

11 Autism Research Program/Genetics and Genomics Research Laboratory, Ongwanada Resource Centre, 191 Portsmouth Ave, Kingston, ON, Canada, K7M 8A6

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Behavioral and Brain Functions 2012, 8:19  doi:10.1186/1744-9081-8-19

Published: 4 May 2012



The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males.


We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility.


There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing.


Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.

Autism spectrum disorders; Dopamine receptors; DARPP-32; Association study; Candidate gene