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Multivariate genome-wide association study identifies 1735 unique genetic loci associated with cortical morphology.

By Alexey A Shadrin, Tobias Kaufmann, Dennis van der Meer, Clare E. Palmer, Carolin Makowski, Robert John Loughnan, Terry L Jernigan, Tyler M. Seibert, Donald J. Hagler, Olav B Smeland, Yunhan Chu, Aihua Lin, Weiqiu Cheng, Guy Hindley, Wesley K Thompson, Chun Chieh Fan, Dominic Holland, Lars T Westlye, Oleksandr Frei, Ole A Andreassen, Anders M Dale

Posted 23 Oct 2020
bioRxiv DOI: 10.1101/2020.10.22.350298

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we exploit the distributed nature of genetic effects across the brain and apply the Multivariate Omnibus Statistical Test (MOSTest) to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) measures from N=35,657 participants in the UK Biobank. We identified 1598 loci for cortical surface area and 1054 for cortical thickness, reflecting an approximate 10-fold increase compared to the most recent report using commonly applied GWAS methods. Our power analysis indicates that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional GWAS approaches. Our gene-based analyses implicate 10% of all protein-coding genes and point towards pathways involved in neurogenesis and cell differentiation, supporting that we are capturing valid biological mechanisms underlying brain anatomy. ### Competing Interest Statement Dr. Andreassen has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests.

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