The role of dopamine-related genes in autism spectrum disorders: Evidence for specific genes and risk for ASD in families with affected males
Hettinger, Joseph Alan
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Individuals with autism spectrum disorders (ASDs) are impaired in cognitive processes and emotional regulation, and exhibit stereotyped behaviours. Dopamine (DA) modulates executive functions, learning, memory, emotional processing and social cognition; all of which are impaired in individuals with ASDs. Because DA modulates a number of processes that are impaired in individuals with ASDs, genes in the dopaminergic pathway are good candidates for genes influencing autistic behaviours. As our previous findings suggested a role for a dopamine-related gene in families with only affected males, this thesis describes a comprehensive study of five genes affecting DA synthesis, levels and function in mothers and affected males with ASDs in an initial TEST cohort of 112 male-only affected sib-pair families as well as a replication study in three additional male-only family cohorts. I genotyped three to five polymorphisms in the TH, SLC6A3, DRD1, DRD2 and PPP1R1B genes and performed population-based single marker case-control comparisons, family-based association tests, quantitative transmission disequilibrium tests as well as haplotype-based analyses and tests for gene-gene interactions. I found evidence for association of the DRD1 (P=0.0027-0.040), DRD2 (P=0.0002-0.007) and PPP1R1B (P=0.00042-0.001) genes with autism in affected males from the TEST cohort. Evidence for DA-related gene interactions were found between polymorphisms in DRD1, DRD2 and PPP1R1B (P=0.0094-0.012) in affected males relative to a comparison group. Furthermore, I found that polymorphisms in the TH and DRD1 genes were associated with the risk for mothers having sons with ASD in the TEST families (P=0.007-0.025) and putative risk alleles in DRD1 and DRD2 were preferentially transmitted from mothers (P=0.016) and fathers (P=0.023) respectively, to affected children. All findings remained significant following corrections for multiple testing. The TEST cohort findings were not replicated in other family cohorts. However, an examination of dysmorphology data for the different family sets revealed phenotypic differences and thus, genetic differences are to be expected. In summary, I found evidence for a contribution of DA-related genes in a specific family cohort with ASDs. Additional functional and phenotypic studies will enable a better understanding of the contributions and implications of these findings to our understanding of autism.