12The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P ≤ 5 x 10 -8 ); 199 survived multiple testing correction (P ≤ 8.3 x 10 -10 ; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression and ADHD.One Sentence Summary: Common genetic variation is associated with inter-individual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.The human cerebral cortex is the outer grey matter layer of the brain, which is implicated in multiple aspects of higher cognitive function. Its distinct folding pattern is characterised by convex (gyral) and concave (sulcal) regions. Computational brain mapping approaches use the consistent folding patterns across individual cortices to label brain regions(1). During fetal development excitatory neurons, the predominant neuronal cell-type in the cortex, are generated from neural progenitor cells in the developing germinal zone(2). The radial unit hypothesis(3) posits that the expansion of cortical surface area (SA) is driven by the proliferation of these neural progenitor cells, whereas thickness (TH) is determined by the number of neurogenic divisions. Variation in global and regional measures of cortical SA and TH are associated with neuropsychiatric disorders and psychological traits(4) ( Table S1). Twin and family-based brain imaging studies show that SA and TH measurements are highly heritable and are largely influenced by independent genetic factors(5). Despite extensive studies of genes impacting cortical structure in model organisms (6), our current understanding of genetic variation impacting human cortical size and patterning is limited to rare, highly penetrant variants (7,8). These variants often disrupt cortical development, leading to altered post-natal structure. However, little is known about how common genetic variants impact human cortical SA and TH.To address this, we conducted genome-wide association meta-analyses of cortical SA and TH measures in 51,662 individuals from 60 cohorts from around the world (Tables S2-S4). Cortical measures were extracted from structural brain MRI scan...

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.

A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.

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