CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice
Authors: Sanchez-Roige Sandra , Jennings Mariela V. , Thorpe Hayley H. A. , Mallari Jazlene E. , van der Werf Lieke C. , Bianchi Sevim B. , Huang Yuye , Lee Calvin , Mallard Travis T. , Barnes Samuel A. , Wu Jin Yi , Barkley-Levenson Amanda M. , Boussaty Ely C. , Snethlage Cedric E. , Schafer Danielle , Babic Zeljana , Winters Boyer D. , Watters Katherine E. , Biederer Thomas ,   23andMe Research Team, Aslibekyan Stella , Auton Adam , Babalola Elizabeth , Bell Robert K. , Bielenberg Jessica , Bryc Katarzyna , Bullis Emily , Coker Daniella , Partida Gabriel Cuellar , Dhamija Devika , Das Sayantan , Filshtein Teresa , Fletez-Brant Kipper , Freyman Will , Heilbron Karl , Gandhi Pooja M. , Hicks Barry , Hinds David A. , Jewett Ethan M. , Jiang Yunxuan , Kukar Katelyn , Lin Keng-Han , Lowe Maya , McCreight Jey C. , McIntyre Matthew H. , Micheletti Steven J. , Moreno Meghan E. , Mountain Joanna L. , Nandakumar Priyanka , Noblin Elizabeth S. , O’Connell Jared , Petrakovitz Aaron A. , Poznik G. David , Schumacher Morgan , Shastri Anjali J. , Shelton Janie F. , Shi Jingchunzi , Shringarpure Suyash , Tran Vinh , Tung Joyce Y. , Wang Xin , Wang Wei , Weldon Catherine H. , Wilton Peter , Hernandez Alejandro , Wong Corinna , Tchakouté Christophe Toukam , Mackillop James , Stephens David N. , Elson Sarah L. , Fontanillas Pierre , Khokhar Jibran Y. , Young Jared W. , Palmer Abraham A. 
Published: May 2023

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.