Genetic architecture of subcortical brain structures in 38,851 individuals.

TitleGenetic architecture of subcortical brain structures in 38,851 individuals.
Publication TypeJournal Article
Year of Publication2019
AuthorsSatizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL, Scholz M, Sargurupremraj M, Jahanshad N, Roshchupkin GV et al.
JournalNat Genet
Volume51
Issue11
Pagination1624-1636
Date Published2019 Nov
ISSN1546-1718
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.

DOI10.1038/s41588-019-0511-y
Alternate JournalNat. Genet.
PubMed ID31636452
Grant ListK99MH102357 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH117601 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
5R01MH094524 and P20GM103472 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
K99MH116115 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH111671 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
R01AG059874 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R03 AG054936 / AG / NIA NIH HHS / United States
K01 AG049050, R01 AG061788, P30 AG10133 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
AG047866 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
P30 AG010133, R01 AG019771 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R01AG033193, R01AG050631, U01AG046161, R01AG053960 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R56 AG058854, RF1 AG041915, U01 AG024904, P01 AG026572 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
14848 / / Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation) /
AARF-17-532877 / / Alzheimer's Association / United States
Ramalingaswami Re-entry Fellowship / / Department of Biotechnology, Ministry of Science and Technology (DBT) /
1102821 / / Department of Health | National Health and Medical Research Council (NHMRC) /
APP1095127 / / Department of Health | National Health and Medical Research Council (NHMRC) /
1037196 / / Department of Health | National Health and Medical Research Council (NHMRC) /
WI 3342/3-1 / / Deutsche Forschungsgemeinschaft (German Research Foundation) /
PI14/00918 / / Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III) /
Veni grant 91619115 / / Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) /
CSA-SI/0012/2017 / / MOH | National Medical Research Council (NMRC) /
BROD.FID3668413 / / Mrs Gladys Row Fogo Charitable Trust (Row Fogo Charitable Trust) /
NIH 1 U24 RR021992, NIH 1 U24 RR025736-01 / / U.S. Department of Health & Human Services | NIH | National Center for Research Resources (NCRR) /
C06RR029965 / / U.S. Department of Health & Human Services | NIH | National Center for Research Resources (NCRR) /
UL1 TR000153 / TR / NCATS NIH HHS / United States
MC_UU_00011/1 / / RCUK | MRC | Medical Research Foundation /
223273, 248778, 262656, 275054 / / Norges Forskningsråd (Research Council of Norway) /
Career Award / / Burroughs Wellcome Fund (BWF) /