CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

Abstract

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. 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 single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS (“MouseWAS”) by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6–11%), and moderate genetic correlations (rg = 0.20–0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

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

“…However, 14 of these loci map to genes previously associated with these traits through positional mapping of independent loci or gene‐based tests (Table 2). The top association in the sensation seeking GWAS was an intronic CADM2 variant (rs2069123, P = 8.85 × 10 −98 ) identified in prior GWAS of related traits 21,22,53,54 . The alcohol consumption GWAS ($$$ \hat{N} $$$ = 1,388,120; ζ g = 0.040, SE = 0.002) detected 842 independent GWS SNPs constituting 188 independent genomic loci (Tables S10 and S11).…”

“…In the sensation seeking GWAS ($$$ \hat{N} $$$ = 710,971; ζ g = 0.087, SE = 0.003), 1092 independent GWS variants, mapped to 262 independent genomic loci, were identified (Tables S7 and S8). Thirty‐one genomic loci (~12%) represented novel loci that were not (A) associated with or in LD ( r 2 > .1) with SNPs associated with any of the three sensation seeking indicator GWAS, (B) previously associated with any trait for studies included in the NHGRI‐EBI GWAS catalogue (version 104: 2021‐09‐15), 52 and (C) not identified in other recently conducted trait‐relevant GWAS (e.g., impulsive personality traits 53 and externalising behaviour 54 ; Table S9). However, 14 of these loci map to genes previously associated with these traits through positional mapping of independent loci or gene‐based tests (Table 2).…”

Genome-Wide Association Studies of Coffee Intake in UK/US Participants of European Ancestry Uncover Gene-Cohort Influences

“…Study cohorts, coffee intake and univariate GWAS 23andMe. Univariate GWAS was conducted in a sample of 130,153 male and female research participants of the genetics testing company 23andMe, Inc, as previously described 155 .…”

“…Univariate GWAS was conducted in a sample of 130,153 male and female research participants of the genetics testing company 23andMe, Inc, as previously described 155 . Participants provided informed consent and volunteered to participate in the research online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent (E&I) Review Services.…”

“…The 23andMe pipeline removes variants of low genotyping quality (failed a Mendelian transmission test in trios ( p <1.00E-20), failed Hardy- Weinberg test ( p <1.02E-20), failed batch effects test (ANOVA p <1.00E-20), or had a call rate <90%) or imputation quality (r 2 <0.50 averages across genotyping arrays or a minimum r 2 <0.3 or variants with apparent batch effects ( p <1.00E-50)) 157,159 . The 23andMe GWAS pipeline performs linear regression and assumes an additive model for allelic effects 43,155,160,161 . Only unrelated participants were included in the GWAS, which was determined using a segmental identity-by-descent ( IBD ) estimation algorithm.…”