Conditional False Discovery Rate Analysis Of Genome-Wide Association Studies Uncovers Genetic LOCI Shared Between Schizophrenia And Volumes Of Hippocampus, Putamen And Intracranial Volume

Abstract

Schizophrenia (SCZ) is a severe mental disorder associated with differences in subcortical brain volumes and intracranial volume (ICV). However, the molecular mechanisms underlying these brain abnormalities are poorly understood. Subcortical brain structures regulate a variety of higher-order functions including emotion, movement, cognition, and reward-seeking behavior. Moreover, the majority of dopamine D2-receptors targeted by antipsychotic drugs are located in the basal ganglia, and treatment with antipsychotics may alter the volumes of the basal ganglia and the hippocampus. Hence, elucidating whether SCZ and brain structure volumes share causative factors may provide important insights into SCZ pathogenesis and its relationship to brain structure formation. Both SCZ and brain structure volumes have high heritability estimates (60-80% and 70–90%, respectively), and brain volume alterations are also present in unaffected relatives of patients with SCZ, suggesting that genetic risk underlying SCZ may also influence brain structure volumes. Despite this, a recent study reported no evidence of shared genetic influences between subcortical brain volumes and SCZ after using a battery of (frequentist) statistical tools to analyze genome-wide association study (GWAS) data of these phenotypes (Franke et al, 2016).Here, we used an alternative approach to address the question of genetic overlap, by applying the conditional false discovery rate (cFDR) approach. This statistical framework increases power for discovery by leveraging overlapping signal across GWAS. Importantly, cFDR analysis allows for identifying overlapping loci regardless of their direction of allelic effects. Applying the cFDR methodology, we have previously demonstrated shared genetic variants between SCZ, Alzheimer’s disease, immune-related diseases and related phenotypes, and substantially increased the number of identified risk loci. Here, we analyzed summary data (p-values and z-scores) from GWAS on seven subcortical brain volumes and ICV (n=11,840) from the ENIGMA Consortium (Enhancing NeuroImaging Genetics through Meta-Analysis) and GWAS on SCZ (n=82,315) from PGC (Psychiatric Genomics Consortium). To validate our approach and assess the replicability of the identified variants, we studied them in larger GWAS samples on ICV and hippocampal volume (n≥26,577).We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional cFDR<0.05, we identified two loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), two loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and two loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). Three of the six identified loci are novel for SCZ. The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, two loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. In conclusion, the findings indicate that SCZ and volumes of hippocampus, putamen and ICV share genetic influences. The results provide new insights into the common genetic architecture underlying SCZ and brain structure formation, suggesting novel molecular genetic mechanisms.