Genome-wide association studies of impulsive personality traits (BIS-11 and UPPS-P) and drug experimentation in up to 22,861 adult research participants identify loci in the CACNA1I and CADM2 genes

Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse and attention-deficit/hyperactivity disorder (ADHD). In collaboration with the genetics company 23andMe, we performed 10 genome-wide association studies on measures of impulsive personality traits [the short version of the UPPS-P Impulsive Behavior Scale, and the Barratt Impulsiveness Scale (BIS-11)] and drug experimentation (the number of drug classes an individual had tried in their lifetime) in up to 22,861 male and female adult human research participants of European ancestry. Impulsive personality traits and drug experimentation showed single nucleotide polymorphism heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with UPPS-P Sensation Seeking (p = 8.3 × 10^-9, rs139528938) and showed a suggestive association with Drug Experimentation (p = 3.0 × 10^-7, rs2163971; r² = 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p = 3.8 × 10^-8; rs199694726). The role of these genes was supported by single variant, gene- and transcriptome-based analyses. Multiple subscales from both UPPS-P and BIS showed strong genetic correlations (>0.5) with Drug Experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPS-P and BIS subscales were genetically correlated with ADHD (r_g = 0.30-0.51), supporting their validity as endophenotypes. Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.