Trans-ancestry meta-analysis of genome wide association studies of inhibitory control

• Published in: Molecular psychiatry 2023-10, Vol.28 (10), p.4175-4184
• Main Authors: Arnatkeviciute, Aurina, Lemire, Mathieu, Morrison, Claire, Mooney, Michael, Ryabinin, Peter, Roslin, Nicole M., Nikolas, Molly, Coxon, James, Tiego, Jeggan, Hawi, Ziarih, Fornito, Alex, Henrik, Walter, Martinot, Jean-Luc, Martinot, Marie-Laure Paillère, Artiges, Eric, Garavan, Hugh, Nigg, Joel, Friedman, Naomi P., Burton, Christie, Schachar, Russell, Crosbie, Jennifer, Bellgrove, Mark A.
• Format: Article
• Language: English
• Subjects: 45/43; 631/378; 631/477; Attention deficit hyperactivity disorder; Behavioral Sciences; Biological Psychology; Cognitive ability; Endophenotypes; Executive Function; Genetic analysis; Genetic diversity; Genetic factors; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Genome-Wide Association Study - methods; Genomes; Heritability; Humans; Life Sciences; Medicine; Medicine & Public Health; Mental disorders; Meta-analysis; Multifactorial Inheritance; Multifactorial Inheritance - genetics; Neurosciences; Pharmacotherapy; Phenotypes; Polygenic inheritance; Polymorphism, Single Nucleotide; Polymorphism, Single Nucleotide - genetics; Psychiatry; Reaction time task; Schizophrenia; Schizophrenia - genetics; Single-nucleotide polymorphism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-023-02187-9

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries ( N  = 14,877) using cognitive traits derived from the stop-signal task, namely – go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.