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.

Fig. 1 ∣. Heritability and Manhattan plot of genetic variants associated with subcortical brain volumes in the European sample.

a, Family-based heritability (h²) estimates were performed with SOLAR in the FHS (n = 895) and ASPS-Fam (n = 370). b. Combined Manhattan plot highlighting the most significant SNPs across all subcortical structures (nucleus accumbens, n = 32,562; amygdala, n = 34,431; brainstem, n = 28,809; caudate, n = 37,741; pallidum, n = 34,413; putamen, n = 37,571; thalamus, n = 34,464). Variants are colored differently for each structure as in a. Linear regression models were adjusted for sex, age, age², total intracranial volume (CHARGE and ENIGMA) or total brain volume (UK Biobank), and population stratification. The solid horizontal line denotes genome-wide significance, as set in this study after additional Bonferroni correction for six independent traits (P < 5 × 10⁻⁸/6 = 8.3 × 10⁻⁹ for two-sided tests). The dashed horizontal line denotes the classic genome-wide threshold of P < 5 × 10⁻⁸. Individual Manhattan plots are provided in the Supplementary Note.

Fig. 2 ∣. Partitioning heritability by functional annotation categories.

Analyses performed in the European sample (nucleus accumbens, n = 32,562; amygdala, n = 34,431; brainstem, n = 28,809; caudate, n = 37,741; pallidum, n = 34,413; putamen, n = 37,571; thalamus, n = 34,464). Plotted ellipses represent enrichment (proportion of h²_g explained/proportion of SNPs in a given functional category) for subcortical structures (y axis) across 28 functional categories (x axis). The color bar indicates the magnitude and direction of enrichment. Starred pairs denote significant over-representation after Bonferroni correction for 168 tests (28 annotation categories and six independent traits; P < 3 × 10⁻⁴). CTCF, CCCTC-binding factor; DGF, digital genomic footprint; DHS, DNase I hypersensitivity site; PGC2, Psychiatric Genomics Consortium; TFBS, transcription-factor-binding sites; TSS, transcription start site; UTR, untranslated region. Sources represented on the x axis are described in ref. .

Fig. 3 ∣. Protein–protein interaction network of 148 genes enriched for common variants influencing the volume of subcortical structures.

The arrowheads represent protein–protein associations, where the edge color indicates the predicted mode of action (bright green, activation; pink, post-translational modification; red, inhibition; dark blue, binding, purple, catalysis; light blue, phenotype; black, reaction; yellow, transcriptional regulation) and the arrowhead shape represents the predicted action effects (pointed arrow, positive; flat arrow, negative; oval arrow, unspecified). Colored nodes represent the queried proteins and first shell of interactors (five maximum), whereas white nodes represent the second shell of interactors (five maximum).