Genetic architecture of subcortical brain structures in 38,851 individuals

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.

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Fig. 1: Heritability and Manhattan plot of genetic variants associated with subcortical brain volumes in the European sample.
Fig. 2: Partitioning heritability by functional annotation categories.
Fig. 3: Protein–protein interaction network of 148 genes enriched for common variants influencing the volume of subcortical structures.

Data availability

The genome-wide summary statistics that support the findings of this study are available from the CHARGE dbGaP (accession code: phs000930) and ENIGMA (http://enigma.ini.usc.edu/research/download-enigma-gwas-results) websites.

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Acknowledgements

We thank all of the study participants for contributing to this research. Full acknowledgements and grant support details are provided in the Supplementary Note.

Author information

C.L.S. drafted the manuscript with contributions from H.H.H.A., D.P.H., C.C.W., T.V.L., A.A.-V., S.Ehrlich., A.K.H., M.W.V., D.J., T.G.M.v.E., C.D.W., M.J.W., S.E.F., K.A.M., P.J.H., B.F., H.J.G., A.D.J., O.L.L., S.Debette, S.E.M., J.M.S., P.M.T., S.S. and M.A.I. M.S., N.J., L.R.Y., T.V.L., G.C., L.A., M.E.R., A.d.B., I.K., M.A., S.A., S.E., R.R.-S., A.K.H., H.J.J., A.Stevens., J.B., M.W.V., A.V.W., K.W., N.A., S.H., A.L.G., P.H.L., S.G., S.L.H., D.K., L.Schmaal, S.M.L., I.A., E.W., D.T.-G., J.C.I., L.N.V., R.B., F.C., D.J., O.C., U.K.H., B.S.A., C.-Y.C., A.A.A., M.P.B., A.F.M., S.K.M., P.A., A.J.Schork., D.C.M.L., T.Y.W., L.Shen, P.G.S., E.J.C.d.G., M.T., K.R.v.E., N.J.A.v.d.W., A.M.M., J.S.R., N.R., W.H., M.C.V.H., J.B.J.K., L.M.O.L., A.Hofman, G.H., M.E.B., S.R., J.-J.H., A.Simmons, N.H., P.R.S., T.W.M., P.Maillard, O.Gruber, N.A.G., J.E.S., H.Lemaître, B.M.-M., D.v