An Atlas of Genetically Correlated Regions of The Human Cortex: Findings From The Enigma Consortium

Abstract

The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium has completed the first phase of the largest GWAS of the human cortex, currently comprised of >20,000 subjects with genome-wide genotyping and structural brain imaging. This latest effort builds on prior projects by the ENIGMA Consortium which assessed common genetic influences on subcortical and global brain volume measures (Hibar et al., 2015 Nature). Here we expand our focus to examine the common genetic determinants of cortical thickness and surface area in 68 regions spanning the entire human cortex. We identified several novel genetic variants with the most significant associations in the lateral occipital and pericalcarine gyri.These cortical findings (and prior work on subcortical brain structures) within the ENIGMA Consortium provide a rich substrate of data to develop and test novel methods to better understand the biology of the brain and disease processes. Here we developed a novel genetic clustering approach that combines LDSC regression with unsupervised clustering applied to adjacency matrices to build an atlas of genetically correlated regions across the cortex. This identifies clusters of brain regions with genetically similar developmental origins. By adding subcortical brain regions, we identify a “genetic connectivity matrix” of subcortical brain volumes and cortical regions with the highest genetic similarity. This atlas provides a novel, data-driven parcellation of the brain to better understand the genetics of complex behaviors subserved by functionally or genetically related brain regions.To evaluate the genetically correlated brain regions for suitability as biomarkers for complex behaviors, we measured the genetic correlation using LDSC regression between each brain region GWAS and GWAS for schizophrenia (Ripke et al., 2014 Nature) and other major psychiatric disorders. These results suggest a possible link between genetically related regions in the frontal cortex and susceptibility to schizophrenia.The findings discussed here represent the largest effort to date to build an atlas defined by genetically correlated brain regions and evaluate genetic relationships among cortical brain regions and several major psychiatric disorders including schizophrenia. These results provide insights into the genetic architecture of the brain and represent a valuable resource for understanding the relationship between brain measures and behavior.