The limited utility of employing categorical diagnoses in genetic studies of complex psychiatric disorders has led the field to explore dimensional measures of functional neurocognitive phenotypes as more proximal to brain biology. A promising candidate for the study of impulsivity-related mental illness is the construct of inhibitory cognitive control (ICC). Research has shown that impaired ICC, manifest behaviorally as impulsivity, is a core feature of disorders such as attention-deficit/hyperactivity (ADHD) and bipolar (BPD) disorders. Our primary aim is to examine whether alleles associated with ICC in healthy individuals can explain a portion of the genetic risk for ADHD and BPD. We will explore ICC in an extensively phenotyped healthy control population of 1600 individuals. Quantitative measures of impulsive choice and impulsive action, respectively using the delayed discounting task (DDT) and stop signal task (SST), have been assessed in this sample, and will be combined to create a measure of ICC. A genome-wide polygenic risk score for ICC will be validated in two independent samples. Correlation between ICC polygenic risk in the LA2K dataset and publicly available psychiatric populations will test for shared genetic risk. We hypothesize that those disorders where impulse control is a core feature, such as ADHD and BPD, will show greater genetic overlap with ICC phenotypes than other disorders. Furthermore, we seek to establish genetic ties to functional gene networks by testing ICC- associated variants for enrichment in ICC-related genetic pathways. This project will support ICC as a key, inherited trait conferring vulnerability to impulsivity-related mental illness and may ultimately suggest new avenues for behavioral and pharmacological interventions that target ICC.
Mental illness may be better conceptualized as overlapping symptom spectra rather than discrete, separate diagnoses. Inhibitory cognitive control, a core feature of impulsivity-related disorders such as attention- deficit/hyperactivity and bipolar disorders, may present a more tractable, biologically relevant proxy for cross- disorder genetic studies. We propose to test whether the collection of genetic variants conferring cumulative risk for inhibitory cognitive control will be enriched in individuals with impulsivity-related psychiatric disorders.
