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

Abstract

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 ϭ 8.3 ϫ 10 Ϫ9 , rs139528938) and showed a suggestive association with Drug Experimentation (p ϭ 3.0 ϫ 10 Ϫ7 , rs2163971; r 2 ϭ 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p ϭ 3.8 ϫ 10 Ϫ8 ; 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 (Ͼ0.5) 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 ϭ 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.

The Latent Genetic Structure of Impulsivity and its Relation to Internalizing Psychopathology

“…Third, the GWAS data used here reflect ascertainment strategies that may bias our results. For example, the cohorts were generally older, had higher socioeconomic status than the general population, and may have lower than average levels of impulsivity (Sanchez-Roige et al, 2019). In addition, current findings cannot be used to draw inferences about variation among individuals of non-European ancestry, reflecting the underrepresentation of non-Europeans in the field of human genetics.…”

“…IPTs also appear to be genetically dissociable. The largest genome-wide association study (GWAS) of IPTs to date (Sanchez-Roige et al, 2019) showed only moderate genetic correlations between UPPS-P and BIS subscales. In addition, the UPPS-P "sensation seeking" scale was only weakly genetically correlated with other IPTs, but was instead more strongly genetically correlated with extraversion.…”

“…The aims of this study were three-fold (Figure 1). First, we leveraged data from our GWAS of UPPS-P and BIS (Sanchez-Roige et al, 2019) to examine the latent genetic structure of impulsivity; namely we tested multiple competing hypotheses about whether single or multiple genetic factors are needed to capture the genetic structure of IPTs. The UPPS-P THE GENETIC STRUCTURE OF IMPULSIVITY 5 "negative urgency" and "positive urgency" subscales are often considered two facets of a higherorder factor reflecting emotion-based rash action, given their phenotypic similarities (Cyders & Smith, 2007;Littlefield et al, 2016).…”

“…Second, we examined whether delay discounting (DD) could be modeled as a common or separate genetic factor. We hypothesized that DD could be an indicator of lack of premeditation, based on previous work showing strong genetic correlations between the two facets (Sanchez-Roige et al, 2019). DD captures the valuation of future versus present rewards whereas lack of premeditation captures the tendency to act without thinking about future consequences.…”

National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies

“…A recent initiative that may benefit from the use of big data is the collaboration with the genetics company 23andMe, Inc., that some laboratories have used to perform one of the largest GWASs to study impulsive personality traits and examine genetic correlations with drug experimentation and related phenotypes in archival datasets. 65,66 7.3 | Animal studies are necessary in the field of addiction genetics, and more emphasis should be placed on the harmonization of human and animal studies…”