Research

Behavioral and Brain Functions

, 8:19

Open Access This content is freely available online to anyone, anywhere at any time.

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 HettingerAffiliated withDepartment of Physiology, Queen’s University
  • , Xudong LiuAffiliated withQueen’s Genetics and Genomics Lab at Ongwanada, Ongwanada Resource CentreDepartment of Psychiatry, Queen’s University
  • , Melissa L HudsonAffiliated withQueen’s Genetics and Genomics Lab at Ongwanada, Ongwanada Resource CentreDepartment of Psychiatry, Queen’s UniversityAutism Spectrum Disorders – Canadian-American Research Consortium
  • , Alana LeeAffiliated withQueen’s Genetics and Genomics Lab at Ongwanada, Ongwanada Resource CentreDepartment of Psychiatry, Queen’s UniversityAutism Spectrum Disorders – Canadian-American Research Consortium
  • , Ira L CohenAffiliated withAutism Spectrum Disorders – Canadian-American Research ConsortiumDepartment of Psychology and George A. Jervis Clinic, New York State Institute for Basic Research in Developmental Disabilities
  • , Ron C MichaelisAffiliated withDepartment of Biology, Western Carolina University
  • , Charles E SchwartzAffiliated withCenter for Molecular Studies, Greenwood Genetic Center
  • , Suzanne ME LewisAffiliated withAutism Spectrum Disorders – Canadian-American Research ConsortiumDepartment of Medical Genetics, University of British ColumbiaB.C. Child and Family Research Institute
  • , Jeanette JA HoldenAffiliated withDepartment of Physiology, Queen’s UniversityQueen’s Genetics and Genomics Lab at Ongwanada, Ongwanada Resource CentreDepartment of Psychiatry, Queen’s UniversityAutism Spectrum Disorders – Canadian-American Research ConsortiumCentre for Neuroscience Studies, Queen’s UniversityAutism Research Program/Genetics and Genomics Research Laboratory, Ongwanada Resource Centre Email author 

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

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