Understanding the genetic determinants of the brain with MOSTest

• Published in: Nature communications Vol. 11; no. 1; p. 3512
• Main Authors: van der Meer, Dennis, Frei, Oleksandr, Kaufmann, Tobias, Shadrin, Alexey A., Devor, Anna, Smeland, Olav B., Thompson, Wesley K., Fan, Chun Chieh, Holland, Dominic, Westlye, Lars T., Andreassen, Ole A., Dale, Anders M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/43; 59; 59/57; 631/208/205/2138; 631/378/2583; Architecture; Biobanks; Brain; Brain - metabolism; Computational neuroscience; Female; Genetic analysis; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Humanities and Social Sciences; Humans; Loci; Morphology; multidisciplinary; Multivariate Analysis; Nervous System - cytology; Nervous System - metabolism; Neural coding; Regional analysis; Regional development; Science; Science (multidisciplinary); Statistical tests; Statistics; United Kingdom > UK
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17368-1

Regional brain morphology has a complex genetic architecture, consisting of many common polymorphisms with small individual effects. This has proven challenging for genome-wide association studies (GWAS). Due to the distributed nature of genetic signal across brain regions, multivariate analysis of regional measures may enhance discovery of genetic variants. Current multivariate approaches to GWAS are ill-suited for complex, large-scale data of this kind. Here, we introduce the Multivariate Omnibus Statistical Test (MOSTest), with an efficient computational design enabling rapid and reliable inference, and apply it to 171 regional brain morphology measures from 26,502 UK Biobank participants. At the conventional genome-wide significance threshold of α = 5 × 10 −8 , MOSTest identifies 347 genomic loci associated with regional brain morphology, more than any previous study, improving upon the discovery of established GWAS approaches more than threefold. Our findings implicate more than 5% of all protein-coding genes and provide evidence for gene sets involved in neuron development and differentiation. Regional brain morphology has a complex genetic architecture. Here the authors present MOSTest, a multivariate statistical framework, apply it to UK Biobank data, and discover hundreds of loci associated with regional brain morphology.