The genetic architecture of the human cerebral cortex

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology

“…Our findings further underscore the complex molecular mechanisms shaping the human brain, which we show are largely related to neurodevelopmental processes. Despite the largely independent nature of cortical surface area and thickness suggested by twin studies 1 and weak genetic correlation between them estimated using linkage disequilibrium score regression (LDSR) (rg=-0.32, p=6.5E-12) 3 , we find that the phenotypes share a large proportion of genomic loci. Out of a total of 1598 loci for cortical area and 1054 loci for cortical thickness, 917 loci (52.9% of the total number of unique loci) were overlapping.…”

“…To our knowledge, the present study reports the largest number of loci discovered in any GWAS to date. Despite the lower sample size in our study (N=35K) compared to the current largest brain morphology GWAS (N=50K) 3 , analyzing parcellation-free, vertex-wise data with MOSTest increased the yield of significant loci 8.5-fold for cortical surface area and 21.1-fold for cortical thickness. Of note, while being generally consistent, our protocol differs in a few aspects from the previous GWAS 3 , where global measures were included in the principal analysis and data for cortical regions were averaged across right and left hemispheres.…”

“…Using the Desikan-Killiany parcellation and the min-P approach, 3.7 times more variants were previously associated with cortical surface area than with cortical thickness 3 . Similarly, our MOSTest analysis with ROI data identified 2.5 times more loci for area compared to thickness.…”

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

“…1 and 2. Five of the 6 CSA loci were replicated in an external (ENIGMA consortium) sample 22 . The ENIGMA consortium only analyzed CSA and CTh.…”

Mega-Analysis Methods in ENIGMA: The Experience of the Generalized Anxiety Disorder Working Group

“…Analyses can reveal genetic and environmental influences on healthy and pathological variability in the human brain, providing great potential currently not fully harnessed. As an example, a recent ENIGMA meta-analysis using data from 51,665 subjects identified 187 loci influencing cortical surface area and 12 others influencing thickness (Grasby et al, 2020); in another example, the recent UK Biobank analysis used 3144 imaging-derived traits (Elliott et al, 2018) to find 148 replicable clusters of associations between single nucleotide polymorphisms and these traits. Not all imaging traits are sufficiently well defined and stable to allow reliable quantification for ENIGMA meta or mega-analyses, though.…”