Abstract
Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Original language | English |
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Pages (from-to) | 1624-1636 |
Number of pages | 13 |
Journal | Nature Genetics |
Volume | 51 |
Issue number | 11 |
Early online date | 21 Oct 2019 |
DOIs | |
Publication status | Published - Nov 2019 |
Funding
D.P.H. is currently an employee at Genentech. D.J. has received travel and speaker’s honoraria from Janssen–Cilag, as well as research funding from DFG. R.L.B. is a consultant for Pfizer and Roche. P.A. is a scientific adviser for Genoscreen. T.Y.W. is a consultant and advisory board member for Allergan, Bayer, Boehringer–Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics) and Roche, and is a co-founder of Plano and EyRiS. A.M.M. has received grant support from Eli Lilly, Janssen, Pfizer and the Sackler Trust. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.M.-L. is a member of the advisory board for the Lundbeck International Neuroscience Foundation and Brainsway, a member of the editorial board for the American Association for the Advancement of Science and Elsevier, a faculty member of the Lundbeck International Neuroscience Foundation and a consultant for Boehringer Ingelheim. W.J.N. is the founder and scientific lead of Quantib BV, in addition to being a shareholder. M.M.N. is a shareholder of Life & Brain, receives a salary from Life & Brain, has received support from Shire for attending conferences and has received financial remuneration from the Lundbeck Foundation, Robert Bosch Foundation and Deutsches Ärzteblatt for participation in scientific advisory boards. B.F. has received educational speaking fees from Shire and Medice. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen– Cilag, as well as research funding from Fresenius Medical Care.
Funders | Funder number |
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Fresenius Medical Care | |
Sackler Trust | |
National Institute of Mental Health | 5R01MH094524, K99MH102357, R01MH117601, R01MH111671, K99MH116115, P20GM103472 |
National Institute on Aging | K01 AG049050, R01AG033193, P30 AG010133, U01AG046161, R01AG053960, AG047866, R01 AG019771, R01AG059874, R01AG050631, R03 AG054936, RF1 AG041915, R56 AG058854, U01 AG024904, P01 AG026572, R01 AG061788 |
National Center for Research Resources | NIH 1 U24 RR021992, NIH 1 U24 RR025736-01, C06RR029965 |
Burroughs Wellcome Fund | |
Michael J. Fox Foundation for Parkinson's Research | 14848 |
Alzheimer's Association | AARF-17-532877 |
Eli Lilly and Company | |
Pfizer | |
Janssen Biotech | |
National Center for Advancing Translational Sciences | UL1TR000153 |
Mrs Gladys Row Fogo Charitable Trust | BROD.FID3668413 |
National Health and Medical Research Council | APP1095127, 1037196, 1102821 |
South African Medical Research Council | |
National Medical Research Council | CSA-SI/0012/2017 |
Deutsche Forschungsgemeinschaft | WI 3342/3-1 |
Fonds De La Recherche Scientifique - FNRS | |
Canadian HIV Trials Network, Canadian Institutes of Health Research | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | Veni grant 91619115 |
Instituto de Salud Carlos III | PI14/00918 |
Norges forskningsråd | 223273, 248778, 262656, 275054 |
Medical Research Foundation | MC_UU_00011/1 |
Cohort Studies
- Netherlands Twin Register (NTR)