Fig. 3. Genetic Influences on brain structure: effects of common and rare genetic variants.
ENIGMA’s large-scale genetic analyses study the effects of both common and rare genetic variants on brain measures. a A series of progressively larger genome-wide association studies have revealed over 45 genetic loci associated with subcortical structure volumes (Hibar et al.25, Satizabal et al.14) and over 200 genetic loci associated with cortical thickness and surface area Grasby et al.13. The Manhattan plots here (adapted from Hibar et al.25, show the genome (on the x-axis) and the evidence for association (as a logarithm of the p-value, on the y-axis) for each common genetic variant (or SNP) with the volume of each brain structure shown. b Genetics of Hippocampal Volume. A subsequent genome-wide association study (GWAS) of 33,536 individuals discovered six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, two lie within key genes involved in neuronal migration and microtubule assembly (ASTN2 and MAST4) (Hibar et al.173). An interactive browser, ENIGMA-Vis—http://enigma-brain.org/enigmavis—can be used to navigate ENIGMA’s genomic data. Initially started as a web page to plot ENIGMA summary statistics data for a specific genomic region, ENIGMA-Vis grew over the years into a portal with tools to query, visualize, and navigate the effects, and relate them to other GWAS. c In complementary work on rare variants by the ENIGMA-CNV Working Group, Sønderby and colleagues (2018) examined effects of the 16p11.2 distal CNV that predisposes to psychiatric conditions including autism spectrum disorder and schizophrenia. ENIGMA (including the 16p11.2 European Consortium) and deCODE datasets were combined to discover negative dose-response associations with copy number on intracranial volume and regional caudate, pallidum and putamen volumes—suggesting a neuropathological pattern that may underlie the neurodevelopmental syndromes. The agreement across datasets is apparent in the Forest plots for each brain region. [Data adapted, with permission from the authors and publishers].