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 11
ISSN1546-1718
KeywordsAdult, Aged, Animals, Brain, Cohort Studies, Drosophila melanogaster, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders, Organ Size
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
PubMed Central IDPMC7055269
Grant ListUH3 NS100605 / NS / NINDS NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
UL1 TR000153 / TR / NCATS NIH HHS / United States
MR/S015132/1 / MRC_ / Medical Research Council / United Kingdom
P30 AG010161 / AG / NIA NIH HHS / United States
R01AG059874 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) / International
R00 MH101367 / MH / NIMH NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
U01 HL130114 / HL / NHLBI NIH HHS / United States
MR/M013111/1 / MRC_ / Medical Research Council / United Kingdom
G1001245 / MRC_ / Medical Research Council / United Kingdom
MC_UU_00011/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01MH111671 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
MR/N027558/1 / MRC_ / Medical Research Council / United Kingdom
T32 AG058507 / AG / NIA NIH HHS / United States
MC_UU_00011/1 / / RCUK | MRC | Medical Research Foundation / International
R01MH117601 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
C06RR029965 / / U.S. Department of Health & Human Services | NIH | National Center for Research Resources (NCRR) / International
K99MH116115 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
P30 AG010129 / AG / NIA NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
K99MH102357 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
R03 AG054936 / AG / NIA NIH HHS / United States
R01 MH119243 / MH / NIMH NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States