CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

Abstract

Background: Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology. Methods: We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N=123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N=130,684). Because these GWAS implicated the gene CADM2, we next performed a phenome-wide study (PheWAS) in a multi-ancestral 23andMe cohort (N=3,229,317, European; N=579,623, Latinx; N=199,663, African American). Finally, we produced Cadm2 knock-out mice and tested them using a battery of behavioral impulsivity tasks. Results: In humans, impulsive personality traits showed modest chip-heritability (~6-10%), and moderate genetic correlations (rg=.20-.50) with other personality traits, and various psychiatric and medical traits. We replicated associations from earlier GWAS of these traits and found novel associations including DRD2, CRHR1, FOXP2, TCF4, PTPRF. PheWAS for CADM2 identified associations with 378 traits in European participants, and 47 traits in Latinx participants, replicating associations with risky behaviors, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Cadm2 knock-out mice showed reduced impulsivity in the 5-choice serial reaction time task, while heterozygote mice showed lower risky behavior in the mouse Iowa gambling task. Conclusions: Our results further establish the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries. Additionally, we demonstrate that deletion of Cadm2 in mice influences behavior in assays designed to measure impulsive and risky behavior.

Assessment of Binge-Like Eating of Unsweetened vs. Sweetened Chow Pellets in BALB/c Substrains

“…BALB/c mice have been suggested to be more ''impulsive'' than other inbred strains of mice (Otobe and Makino, 2004), but a direct assessment of impulsivity traits between the two substrains is yet to be explored. Impulsivity has been correlated with substance use disorders and eating disorders (Alcaraz-Iborra and Cubero, 2015;Kessler et al, 2016), particularly in the initiation of addiction behaviors, and has been demonstrated to have genetic components that have been identified in human GWAS (Dawe and Loxton, 2004;Bevilacqua and Goldman, 2013;Salatino-Oliveira et al, 2015;Giorgi et al, 2019;Sanchez-Roige et al, 2022). More specifically, treatment for attention deficit hyperactivity disorder (Lisdexamfetaminedimesylate; Vyvanse), which is stated to improve impulse control, has been shown to decrease binge-like eating (McElroy et al, 2015;Guerdjikova et al, 2016;Griffiths et al, 2021).…”

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

“…The current study is not without limitations. First, limited sample sizes likely hindered analyses of the (lack of) self-control and urgency traits, demonstrating the need for larger IPT GWAS (e.g., Becker et al, 2021;Sanchez-Roige et al, 2022). Second, and equally important, is the exclusion of non-European ancestry samples from the present study.…”

What made us “hunter-gatherers of words”

“…Intriguingly, in the context of this discussion, genes found in the most restrictively defined lists of deserts of introgression in modern human genomes (regions of the genome depleted of introgressed alleles from neanderthals/denisovans) (Reher, 2021 ), such as CADM2 , have been linked to personality traits like risk-taking behavior, impulsivity, addiction (Pasman et al, 2022 ; Sanchez-Roige et al, 2022 ). (Similar signals have been associated with other genes in introgression deserts such as CADPS2 or FOXP2 Sanchez-Roige et al, 2022 ). Of note, the gene ( CADM2 ) is listed alongside glutamate receptor GRIK3 , among the top candidate genes with potential connections to behavior in domestication studies (Freedman et al, 2016 ).…”