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

Abstract

Background Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods Using 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 dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. Results GenomicSEM dual-systems models underscored 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 = 0.60). 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). No significant associations were observed with subcortical phenotypes. Conclusions Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology.

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

“…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.…”

“…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 …”

“…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.…”