Abstract
Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.
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Data availability
Detailed information on how to access publicly available GWAS summary data from the ENIGMA and CHARGE consortia is reported in their corresponding publications2,12,15. Researchers can access individual-level data from the UKB and ABCD cohorts following the corresponding data application procedures. Work performed using UKB data was done under application 25331. Full genome-wide summary statistics generated in the present study are available at the ENIGMA website (http://enigma.ini.usc.edu/research/download-enigma-gwas-results).
Code availability
No custom code was used in this study. Publicly available software tools were used to perform genetic analyses and are referenced throughout the paper.
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Acknowledgements
We thank all the study participants for contributing to this research. Full acknowledgments and grant support details are provided in Supplementary Note.
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Contributions
L.M.G.-M., A.I.C., S.D.-T., J.A.R., Z.C., B.L.M., K.L.G., J.G.T., P.M.T., C.L.S., S.E.M. and M.E.R. conducted the core analysis and wrote the paper. I.A., D.A., O.A.A., A.A.-V., D.A.B., M.P.M.B., D.I.B., H.B., J.K.B., W.C., V.D.C., S.C., B.C.-F., A.M.D., G.I.d.Z., C. DeCarli, C. Depondt, S. Desrivières, S. Ehrlich, T.E., S.E.F., M.F., B.F., H.J.G., O. Gruber, V.G., A.K.H., U.K.H., A.H., S.H., P.J.H., M.K.I., M.A.I., E.G.J., R.S.K., L.J.L., S.M.L., H. Lemaître, P. Mecocci, A.M.-L., T.H.M., M.M.N., N.G.M., P.A.N., J.O., T.P., Z.P., B.W.J.H.P., B.M.P., P.S.S., P.G.S., A.J.S., R.S., G.S., S.S., J.W.S., D.J.S., J.N.T., D.v.E., H.v.B., N.J.A.v.d.W., D.J.V., M.W.V., A.V., H.W., D.R.W., M.W.W., T.W., A.V.W., H.S. and H.V. were the principal investigators of participating cohorts. I.A., S.A., K.A., M.E.B., A.S.B., V.D.C., B.C.-F., F.C., E.J.C.d.G., C. DeCarli, S. Erk, T.E., G.F., I.F., D.A.F., A.L.G., O. Grimm, O. Gruber, V.G., A.K.H., U.K.H., S.H., B.-C.H., A.J.H., N.H., M.A.I., C.R.J., E.G.J., R.S.K., S.M.L., H. Lemaître, D.C.M.L., J.-L.M., V.S.M., K.L.M., P. Mecocci, T.H.M., T.W.M., S.M.M., P.A.N., J.O., M.P., B.W.J.H.P., G.B.P., N.R.-S., P.G.S., G.S., S.S., S.M.S., H.S.S., D.T.-G., J.N.T., M.C.V.-H., D.v.E., N.J.A.v.d.W., M.W.V., H.W., J.M.W., M.W.W., W.W., L.T.W., E.W., T.W., M.P.Z., H.V., I.M., O.L.L., S.R. and W.H. collected the imaging data. I.A., D.A., J.C.B., H.B., J.K.B., J.G.T., V.D.C., C.R.K.C., G.D.S., E.J.C.d.G., P.L.D.J., S. Desrivières, S. Ehrlich, T.E., G.F., I.F., S.E.F., A.J.F., C.F., B.F., H.J.G., K.L.G., N.A.G., O. Gruber, U.K.H., D.P.H., S.H., J.J.H., N.H., M.A.I., J.C.I., N.J., M.J.K., S.M.L., P.H.L., H. Lemaître, H. Lin, W.T.L., M.L., A.F.M., K.A.M., V.S.M., A.M.-L., B.L.M., T.H.M., W.J.N., M.M.N., P.A.N., T.P., B.W.J.H.P., B.M.P., J.I.R., P.S.S., C.L.S., S.I.T., A.J.S., G.S., E.S., S.S., L. Shen, S.M.S., H.S.S., D.J.S., J.L.S., S.I.T., P.M.T., A.W.T., J.N.T., M.W.V., J.M.W., D.R.W., M.W.W., L.T.W., T.W., N.M.-S., N.G.M., J.I.R., L.M.G.-M., A.I.C. and M.E.R. edited the paper. A.S., H.V., M.N., N.J.A., O.L.L. and W.H. contributed to the editing of the paper. S.A., P.A., L.A., R.B., V.D.C., S.C., E.J.C.d.G., P.L.D.J., C. Depondt, S. Desrivières, S. Djurovic, S. Erk, T.E., S.E.F., A.J.F., C.F., R.C.G., O. Gruber, V.G., A.K.H., B.-C.H., G.H., M.A.I., E.G.J., S.L.H., D.C.M.L., J.-L.M., K.A.M., P. Mecocci, T.H.M., T.W.M., M.M.N., P.A.N., B.W.J.H.P., B.M.P., B.P., M.D.R., J.I.R., A.J.S., P.R.S., M. Scholz, S.S., L. Shen, S.M.S., H.S.S., V.M.S., N.J.A.v.d.W., J.V.-B., H.W., I.M., M.N., S.R. and W.H. collected the genetic data. S.A., K.A., R.M.B., O.T.C., M.C., Q.C., C.R.K.C., B.C.-F., F.C., C. DeCarli, S. Desrivières, S. Ehrlich, S. Erk, G.F., I.F., T.G., A.L.G., O. Grimm, N.A.G., A.K.H., U.K.H., D.P.H., S.H., D.F.H., A.J.H., N.J., R.K., D.C.M.L., P. Maillard, A.F.M., K.L.M., S.M.M., K.N., W.J.N., P.A.N., J.O., S.L.R., R.R.-G., G.V.R., P.G.S., C.L.S., L. Schmaal, D.T.-G., M.C.V.-H., D.v.E., N.J.A.v.d.W., L.N.V., H.W., J.M.W., W.W., L.T.W., A.V.W., M.P.Z., A.S., E.F. and O.L.L. conducted the imaging data analysis. L.A., J.C.B., J.G.T., R.M.B., Q.C., C.R.K.C., S.C., E.J.C.d.G., P.L.D.J., S. Debette, S. Desrivières, S. Djurovic, S. Ehrlich, M.F., T.G., K.L.G., N.A.G., D.P.H., E.H., M.K., M.J.K., S.L.H., P.H.L., S.L., D.C.M.L., M.L., Y.M., B.L.M., B.M.-M., K.N., S.L.R., G.V.R., P.G.S., M. Sargurupremraj, C.L.S., R.S., P.R.S., M. Scholz, L. Shen, J.S., A.V.S., D.v.E., D.v.d.M., C.W., J.Y., L.M.G.-M., A.I.C., M.E.R., H.S. and N.J.A. conducted the genetic data analysis.
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I.A. received a speaker’s honorarium from Lundbeck. O.A.A. is a consultant to Cortechs.ai and Precision Health and has received a speaker’s honorarium from Lundbeck, Janssen, Otsuka and Sunovion. H.B. is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes. C.R.K.C. has received past partial research support from Biogen for work unrelated to the topic of this paper. A.M.D. is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a founder of and holds equity in CorTechs Labs and a member of the Scientific Advisory Board of Human Longevity and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. B.F. has received educational speaking fees from Medice. H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen-Cilag, as well as research funding from Fresenius Medical Care. D.P.H. is a full-time employee of Genentech. N.H. is a shareholder in various manufacturers of medical technology. A.M.-L. has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden and von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague and Vitos Klinik Rheingau; and editorial and/or author fees from American Association for the Advancement of Science, ECNP, Servier and Thieme Verlag. W.J.N. is the founder of Quantib BV and was the scientific lead of Quantib BV until 31 January 2023. M.M.N. has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029), and receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities are outside the submitted work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.J.S. receives support from multiple National Institutes of Health (NIH) grants and has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of position emission tomography tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA (Dementia Advisory Board); NIH National Heart, Lung, and Blood Institute (Multi-Ethnic Study of Atherosclerosis Observational Study Monitoring Board); and Springer Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). M. Scholz received funding from Pfizer for a project not related to this research. E.S. received speaker fees from bfd buchholz fachinformationsdienst gmbh. P.M.T. receives partial research support from Biogen for research unrelated to this paper. M.W.W. serves on editorial boards for Alzheimer’s & Dementia and the Journal for Prevention of Alzheimer’s Disease. He has served on advisory boards for Acumen Pharmaceutical, Alzheon, Cerecin, Merck Sharp & Dohme and the NC Registry for Brain Health. He also serves on the University of Southern California (USC) Alzheimer’s Clinical Trials Consortium grant that receives funding from Eisai for the AHEAD study; has provided consulting to Boxer Capital, Cerecin, Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme, NC Registry for Brain Health, Prova Education, T3D Therapeutics, USC and WebMD; has acted as a speaker/lecturer for the China Association for Alzheimer’s Disease and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning, Health Society (Japan), INSPIRE project, U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme, National Center for Geriatrics and Gerontology (Japan) and USC; holds stock options with Alzeca, Alzheon, ALZPath and Anven; and received support for his research from the following funding sources: NIH/National Institute of Neurological Disorders and Stroke/National Institute on Aging, Department of Defense, California Department of Public Health, University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (Healthy Brain Initiative/Brain Health Registry), The Stroke Foundation, and the Veterans Administration. A.I.C. is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, and may hold Regeneron stock or stock options. The other authors declare no competing interests.
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Supplementary Methods and Figs. 1–129, and Acknowledgments.
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García-Marín, L.M., Campos, A.I., Diaz-Torres, S. et al. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries. Nat Genet 56, 2333–2344 (2024). https://doi.org/10.1038/s41588-024-01951-z
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DOI: https://doi.org/10.1038/s41588-024-01951-z
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