Overlap in genetic risk for cross-disorder vulnerability to mental disorders and genetic risk for altered subcortical brain volumes

Abstract

Background: There have been considerable recent advances in understanding the genetic architecture of psychiatric disorders as well as the underlying neurocircuitry. However, there is little work on the concordance of genetic variations that increase risk for cross-disorder vulnerability, and those that influence subcortical brain structures. We undertook a genome-wide investigation of the genetic overlap between cross-disorder vulnerability to psychiatric disorders (p-factor) and subcortical brain structures. Methods: Summary statistics were obtained from the PGC cross-disorder genome-wide association study (GWAS) (Ncase= 232,964, Ncontrol= 494,162) and the CHARGE-ENIGMA subcortical brain volumes GWAS (N=38,851). SNP effect concordance analysis (SECA) was used to assess pleiotropy and concordance. Linkage Disequilibrium (LD) Score Regression and ρ-HESS were used to assess genetic correlation and conditional false discovery (cFDR) was used to identify variants associated with p-factor, conditional on the variants association with subcortical brain volumes. Results: Evidence of global pleiotropy between p-factor and all subcortical brain regions was observed. Risk variants for p-factor correlated negatively with brainstem. A total of 787 LD-independent variants were significantly associated with p-factor when conditioned on the subcortical GWAS results. Gene set enrichment analysis of these variants implicated actin binding and neuronal regulation. Limitations: SECA could be biased due to the potential presence of overlapping study participants in the p-factor and subcortical GWASs. Conclusion: Findings of genome-wide pleiotropy and possible concordance between genetic variants that contribute to p-factor and smaller brainstem volumes, are consistent with previous work. cFDR results highlight actin binding and neuron regulation as key underlying mechanisms. Further fine-grained delineation of these mechanisms is needed to advance the field.