NeuroImage (Dec 2021)
Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology
- Alexey A. Shadrin,
- Tobias Kaufmann,
- Dennis van der Meer,
- Clare E. Palmer,
- Carolina Makowski,
- Robert Loughnan,
- Terry L. Jernigan,
- Tyler M. Seibert,
- Donald J Hagler,
- Olav B. Smeland,
- Ehsan Motazedi,
- Yunhan Chu,
- Aihua Lin,
- Weiqiu Cheng,
- Guy Hindley,
- Wesley K. Thompson,
- Chun C. Fan,
- Dominic Holland,
- Lars T. Westlye,
- Oleksandr Frei,
- Ole A. Andreassen,
- Anders M. Dale
Affiliations
- Alexey A. Shadrin
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Corresponding author at: NORMENT Centre, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, 0424 Oslo, Norway.
- Tobias Kaufmann
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Dennis van der Meer
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, the Netherlands
- Clare E. Palmer
- Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA
- Carolina Makowski
- Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA
- Robert Loughnan
- Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA
- Terry L. Jernigan
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Center for Human Development, University of California San Diego, La Jolla, CA 92037, USA; Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA
- Tyler M. Seibert
- Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92037, USA
- Donald J Hagler
- Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA
- Olav B. Smeland
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Ehsan Motazedi
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Yunhan Chu
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Aihua Lin
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Weiqiu Cheng
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Guy Hindley
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Wesley K. Thompson
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92037, USA
- Chun C. Fan
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA
- Dominic Holland
- Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA
- Lars T. Westlye
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Psychology, University of Oslo, Oslo, Norway
- Oleksandr Frei
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway
- Ole A. Andreassen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Corresponding author at: NORMENT Centre, Building 49, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, 0424 Oslo, Norway.
- Anders M. Dale
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Corresponding author at: Center for Translational Imaging and Precision Medicine, Center for Multimodal Imaging and Genetics, Dept. of Neuroscience and Radiology, University of California San Diego, 9452 Medical Center Dr, La Jolla, CA 92037, United States
- Journal volume & issue
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Vol. 244
p. 118603
Abstract
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 extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.
