We present the largest population-based heritability study of the human brain structural connectome, including a pathology-sensitive extension, the disconnectome. The disconnectome maps the effect of white matter lesions throughout the brain. The connectome and disconnectome were generated from diffusion-weighted images of 3255 unrelated subjects from the Rotterdam Study aged between 45 and 99 years. Graph theory measures were derived for both the connectome and disconnectome. Genotypes were used to derive genetic relationship matrices between individuals for heritability analyses. High measures of heritability, from 33% to 51%, were found across all connectivity measures. The disconnectome showed more significantly heritable connectivity measures than the connectome, suggesting that the new proposed measure may reveal additional or complementary information about the genetic architecture of the human brain.@en

Large-scale distributed analyses of over 30,000 magnetic resonance imaging scans recently detected common genetic variants associated with the volumes of subcortical brain structures. Scaling up these efforts, still greater computational challenges arise in screening the genome for statistical associations at each voxel in the brain, localizing effects using "image-wide genome-wide" testing (voxelwise genome-wide association studies, vGWASs). Here we benefit from distributed computations at multiple sites to metaanalyze genome-wide image-wide data, allowing private genomic data to stay at the site where it was collected. Site-specific tensor-based morphometry is performed with a custom template for each site, using a multichannel registration. A single vGWAS testing 107 variants against 2million voxels can yield hundreds of terabytes (TB) of summary statistics, which would need to be transferred and pooled for metaanalysis. We propose a two-step method, which reduces data transfer for each site to a subset of single-nucleotide polymorphisms and voxels guaranteed to contain all significant hits.@en

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.@en

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/beta-catenin, TGF-beta; and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.@en