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

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.

Making the MOSTest of imaging genetics

“…Through the multivariate GWAS, we found hundreds of independent loci surpassing the conventional wholegenome significance threshold of a=5x10 -8 , improving upon the discovery of all previous GWAS of brain morphology 1,2,14 . Overall, MOSTest led to a threefold higher discovery than the min-P approach, as shown in Figure 1A.…”

“…Regional variations in surface area and thickness of the cerebral cortex, together with the volume of underlying subcortical structures, have been linked to much of our emotion processing and cognitive abilities, as well as the onset and course of devastating brain disorders. These brain morphological features are known to be highly heritable and to have a complex genetic architecture, involving many common genetic variants with small effect sizes 1,2 .…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…For psychiatric disorders where causally implicated brain regions are not known, genetic correlations may help to identify critical regions involved in the pathology. For example, negative genetic correlations have been observed between the volume of the caudate and nucleus accumbens and bipolar disorder ( r g = −0.17 and r g = −0.28, respectively) . Other negative genetic correlations have been observed between global cortical surface area and both major depressive disorder ( r g = −0.13) and ADHD ( r g = −0.17) .…”

“…[78][79][80] While rare variants can have large effects, they do not explain the majority of variability in brain structure within a population. To address this, consortia have recently identified hundreds of genome-wide significant common variant loci, each generally composed of multiple correlated SNPs, that impact human brain structure, including intracranial volume (seven loci), 7,8,[81][82][83] subcortical volumes (38 loci), 6,8,70,81,84,85 ventricular volumes (seven loci), 86 cortical surface area and thickness (150 loci), 74,87 and even white matter anatomy (225 loci). 71 No variants have yet been identified impacting brain function as measured through fMRI, 71 though a handful of variants reach genome-wide significance for oscillatory brain activity as measured with electroencephalograms (two loci).…”

“…For example, negative genetic correlations have been observed between the volume of the caudate and nucleus accumbens and bipolar disorder (r g = −0.17 and r g = −0.28, respectively). 84 Other negative genetic correlations have been observed between global cortical surface area and both major depressive disorder (r g = −0.13) and ADHD (r g = −0.17). 74 Further supporting the negative genetic correlation between cortical surface area and ADHD, intracranial volume, highly correlated with cortical surface area, is also negatively genetically correlated with ADHD risk (r g = −0.23).…”