Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder.

Hart AB, Gamazon ER, Engelhardt BE, Sklar P, Kähler AK, Hultman CM, Sullivan PF, Neale BM, Faraone SV, Psychiatric Genomics Consortium: ADHD Subgroup, de Wit H, Cox NJ, Palmer AA
Proc Natl Acad Sci U S A. 2014 111 (16): 5968-73

PMID: 24711425 · PMCID: PMC4000861 · DOI:10.1073/pnas.1318810111

Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.

MeSH Terms (13)

Attention Deficit Disorder with Hyperactivity Bipolar Disorder Dextroamphetamine Euphoria Genetic Predisposition to Disease Genetic Variation Humans Phenotype Polymorphism, Single Nucleotide Protective Agents Reproducibility of Results Risk Factors Schizophrenia

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