Dual-systems models of the genetic architecture of impulsive personality traits: Neurogenetic evidence of distinct but related factors

Abstract

Background: Dual-systems models provide a parsimonious framework for understanding the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychiatric disorders. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods: Using extant IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between results of multivariate GWAS of dual-systems factors and GWAS of relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were calculated and compared. Results: Evaluation of GenomicSEM model fit indices for dual-systems models suggested that these models highlight important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg=.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g., lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). However, no significant associations were observed for subcortical phenotypes inconsistent with hypothesized functional localization of dual-systems constructs. Conclusions: Dual-systems models of the genetic architecture of IPTs tested here demonstrate evidence of shared and unique genetic influences and associations with relevant neuroimaging phenotypes. These findings emphasize potential advantages in utilizing dual-systems models to study genetic influences for IPTs and transdiagnostic associations with psychiatric disorders.

Neurogenetic and multi-omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder

“…As described previously, 21 GWAS of three phenotypes (adventurousness, 22 risk taking, 22 and UPPS-P sensation seeking 20 ) conducted using primarily 23andMe, Inc. and UK Biobank (UKB) samples were specified as indicators of a sensation seeking genetic factor. Three GWAS were specified as indicators for an alcohol consumption genetic factor: (1) a 'drinks per week' GWAS meta-analysis using summary statistics from 23andMe (N=403,939) and the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN; N=537,341) 23 ; (2) an AUDIT-C GWAS meta-analysis using summary statistics from UKB (N=121,604) 24 and Million Veteran Program (MVP) cohorts (N=200,680) 25 ; and (3) an existing GWAS meta-analysis of grams of alcohol consumed per day using the UKB, Alcohol Genome-Wide (AlcGen) Consortium, and Cohorts for Heart and Aging Research in Genomic Epidemiology Plus (CHARGE+) cohorts.…”

Neurogenetic and multi‐omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder

“…Interestingly, H‐MAGMA dopaminergic midbrain‐specific gene associations for sensation seeking ( BRSK2 ) and both sensation seeking and alcohol consumption ( RUNX1T1 ) highlight genes previously implicated in surface area and sulcal depth 68,69 . Thus, these shared associations between sensation seeking and alcohol consumption point to genes that may have pleiotropic influences on both midbrain dopaminergic neurons and cortical surface area, providing a potential explanation for observed associations between sensation seeking and cortical neuroimaging phenotypes that would be hypothesised as more relevant to ‘top‐down’ cognitive control processes 8,18 …”

“…68,69 Thus, these shared associations between sensation seeking and alcohol consumption point to genes that may have pleiotropic influences on both midbrain dopaminergic neurons and cortical surface area, providing a potential explanation for observed associations between sensation seeking and cortical neuroimaging phenotypes that would be hypothesised as more relevant to 'top-down' cognitive control processes. 8,18 Fifth, important sources of overlap between alcohol consumption and AUD (r g = 0.58) were observed, adding to the literature examining their genetic commonalities and differences. 19,20,28 One source of overlap was the BANK1-SLC39A8 locus, a region of relatively high LD that includes two genes $175 kb apart that code for proteins involved in cellular transport and scaffolding.…”

“…As described previously, 18 GWAS of three phenotypes (adventurousness, 22 risk taking, 22 and UPPS‐P sensation seeking 21 ) conducted using primarily 23andMe, Inc., and UK Biobank (UKB) samples were specified as indicators of a sensation seeking genomic factor. Three GWAS were specified as indicators of an alcohol consumption genomic factor: (1) a ‘drinks per week’ GWAS meta‐analysis using data from 23andMe ( N = 403,939) and the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN; N = 537,341) 23 ; (2) an AUDIT‐C GWAS meta‐analysis using data from UKB ( N = 121,604) 24 and Million Veteran Program (MVP) cohorts ( N = 200,680) 25 ; and (3) an existing GWAS meta‐analysis of grams of alcohol consumed per day using UKB, the Alcohol Genome‐Wide (AlcGen) Consortium, and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus (CHARGE+) Consortium 26 .…”

“…For example, studies have demonstrated associations between sensation seeking and neuroanatomical differences in frontocingulate thickness and surface area, volume of basal ganglia structures (e.g., nucleus accumbens and globus pallidus), 13,14 and reward-cued connectivity of frontostriatal pathways, 15,16 highlighting many of the same regions and circuits associated with the described binge/intoxication stage. As some of these observed differences extend beyond hypothesised subcortical regions used to characterize sensation seeking as a 'bottom-up' process and clearly implicate relevant cortical features, 13,17,18 cortical neuroimaging phenotypes (e.g., regional volume, thickness, and surface area), including phenotypes assessing cortical-subcortical connections, may help to explain relations between sensation seeking and alcohol use phenotypes at the neurobiological level.…”