Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Claudia Liliana Satizábal; Hieab H.H. Adams; Derrek P. Hibar; Charles C. White; Jason L. Stein; Markus R. Scholz; Muralidharan Sargurupremraj; Neda Jahanshad; Albert V. Smith; Joshua C. Bis; Xueqiu Jian; Michelle Luciano A; Edith Hofer; Alexander Teumer; Sven J. van der Lee; Jingyun Yang; Lisa R. Yanek; Tom V. Lee; Shuo Li; Yanhui Hu; Jia Yu Koh; John D. Eicher; Sylvane Desrivières; Alejandro Arias Vásquez; Ganesh Chauhan; Lavinia Athanasiu; Miguel E. Rentería; Sungeun Kim; D. Höhn; Nicola J. Armstrong

doi:10.1101/173831

GeneticsbioRxivAug 28, 2017

Preprint

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Claudia Liliana Satizábal iD, Hieab H.H. Adams iD, Derrek P. Hibar iD, Charles C. White iD, Jason L. Stein iD, Markus R. Scholz iD, Muralidharan Sargurupremraj iD, Neda Jahanshad iD, Albert V. Smith iD, Joshua C. Bis iD, Xueqiu Jian iD, Michelle Luciano A iD, Edith Hofer iD, Alexander Teumer iD, Sven J. van der Lee iD, Jingyun Yang iD, Lisa R. Yanek iD, Tom V. Lee, Shuo Li iD, Yanhui Hu iD, Jia Yu Koh iD, John D. Eicher, Sylvane Desrivières iD, Alejandro Arias Vásquez iD, Ganesh Chauhan iD, , Lachlan T. Strike iD

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, 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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