Characterising the shared genetic influences between schizophrenia and subcortical brain regions

Background: Abnormalities in brain structural volumes are well established in schizophrenia (SZ) and have been proposed as an endophenotype for the disorder. Despite increasing interest in the genetic relationship between brain structural volumes and SZ, our knowledge of the genetic overlap between the phenotypes is limited. This study aims to extend our current understanding of the shared genetic influences between SZ and subcortical brain volumes using data from the latest genome-wide association studies for the respective phenotypes (GWAS) and novel statistical approaches. Additionally, we will explore whether the association between schizophrenia and abnormal regional brain volumes is causal in nature. Methods: Summary statistics were obtained from the largest Psychiatric Genomic Consortium (PGC)-SZ GWAS (Ncase = 69,369, Ncontrol = 236,642) and the CHARGEENIGMA-UKBB GWAS of volumetric measures for eight subcortical brain regions (the nucleus accumbens, amygdala, brainstem, caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus), and total intracranial volume (N = 30,983 - 40,380). Single nucleotide polymorphism (SNP) effect concordance analysis (SECA) was used to assess pleiotropy and concordance. Genetic correlation was assessed using linkage disequilibrium score regression (LDSR) and the pleiotropy informed conditional FDR approach was applied to identify SNPs associated with SZ conditional on their association with subcortical brain volumes. Mendelian randomization (MR) was used to test for causal association between SZ and each brain region. Results: There was evidence of global pleiotropy between SZ, and all examined subcortical brain regions. Inverse concordance between the genetic determinants of SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus was observed. Increased statistical power to detect SZ risk loci was shown when conditioning on subcortical brain volumes. There was no significant evidence for a causal effect of any of the examined brain regions on schizophrenia risk. Discussion: These data confirm the shared genetic basis of SZ and specific intracranial and subcortical brain volumes and provide evidence for negative concordance between SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus. Leveraging the genetic overlap between SZ and subcortical brain volumes has the potential to provide novel insights into the biological basis of the disorder