Attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BP) are neuropsychiatric disordersthat can have deleterious lifetime impact. Several candidate genes for these disorders have emerged, butfunctionally significant variants have not yet been identified and replications are sparse. Our premise is thatelucidating the genetic basis of these complex disorders will benefit from analysis of more parsimonious andless heterogeneous endophenotypes. Impaired response inhibition (Rl) (i.e., difficulty suppressing automaticor already initiated responses) is a promising candidate endophenotype for multiple disorders. We proposethat the genes that influence Rl contribute to ADHD and BP susceptibility through effects on the brainsystems mediating inhibitory control, and that most of these have been undetected by previous studies usingsyndromal status as the phenotypic target.Therefore, we plan a study on the biological bases of impaired Rl, in a large sample (n=2000) of healthysubjects drawn from greater Los Angeles. We will administer a battery of Rl and impulsivity-spectrumneurocognitive and self-report measures, analyzing the phenotypes and identifying composite measuresthrough data reduction efforts, including those of the WGS project in this consortium. We will first identifycandidate SNPs in a whole genome association study of the entire sample, and conduct fine mappinganalyses to refine the localization of the most significant associations. We will then select well-validatedcandidate SNPs to genotype in clinical samples that exhibit Rl deficits (n =100 each, ADHD & BP) and 200matched controls, and test for associations with brain structure and function using MRI.Although there are no validated candidate genes pf moderate to large effect in humans for either Rlphenotypes or the diseases for which they are relevant, substantial evidence indicates that dopaminesystems, and D2 dopamine receptors in particular, are important for expression of Rl. However, the specificneural systems that mediate D2-dependent modulation of Rl are unknown. We will therefore use a bacterialartificial chromosome (BAG) rescue strategy to evaluate the role of D2 dopamine receptors (via Drd2 geneexpression) within components of corticostriatal circuitry that mediates Rl in mice. Importantly, these studiesdo not examine the role for DrD2 as a candidate gene for ADHD or BP, rather, we propose that O2-mediatedneuromodulation of corticostriatal circuitry is a candidate mechanism by which genes (still undiscovered)converge to elicit their effects on Rl.Rl deficits are central to ADHD, BP and other disorders (e.g., drug addiction, obesity) that are of publichealth concern and are resistant to current therapies. Clarifying the bases of Rl, at genetic and neuralsystems levels, can advance treatment for these prevalent and often life-threatening disorders.
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