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

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.

Behavioral Effects of Neuronal, Parent-specific Commd1 Knockout in Mice.

In this study we focused on gene expression and behavioral differences in mice with brain-specific Commd1 knockout. Commd1 is an imprinted gene with preferential maternal expression, residing within a larger genomic region previously found to affect sensorimotor gating. In this study, individuals harboring a conditional Commd1 mutant allele were bred with Syn1-Cre animals, paying special attention to the parent of origin of the Commd1 mutation. Analysis of mRNA levels of Commd1 and phenotypic tests, including the open field, sensorimotor gating, and the forced swim test, were conducted on offspring with either maternally or paternally derived Commd1 knockout. We found that measurable Commd1 mRNA knockout occurred only in the maternally derived line and affected stereotypy and depressive-like behavior without differences in total locomotion compared to controls. Interestingly, we found that maternal knockout animals exhibited decreased time swimming and increased time immobile when compared to maternal and paternal wild type, and paternal knockout animals. However, there were no differences in climbing behavior between genotypes. This study demonstrates an in vivo behavioral role for Commd1 for the first time and demonstrates the need for careful interpretation of experimental results involving Cre-based knockout systems.