Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Abstract

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Figure 1

Genetic predisposition score analyses examining the predictive capacity of ENIGMA brain volumetric results on schizophrenia case-control status using different P-value thresholds. X-axis: (a) hippocampus, (b) ICV, (c) nucleus accumbens, (d) amygdala, (e) caudate nucleus, (f) pallidum, (g) putamen, (h) thalamus. Y-axis shows Nagelkerke's R². Positive values indicate SNP effects for increasing brain structure volume and increased risk for schizophrenia. Negative values indicate SNP effects for decreasing brain structure volume in and increased risk for schizophrenia. Significance values are given in Table 2.

Figure 2

Evaluating the genome-wide overlap between genetic influences on schizophrenia and subcortical volumes. (a) A cartoon describing the output map. (b-i) independent SNPs present in both ENIGMA and PGC schizophrenia results were selected independent of association to any phenotype (see on-line methods). Association results were ordered based on the significance of their association to the phenotype (–log₁₀(P-value) multiplied by the sign of the effect), and statistical significance was evaluated using RRHO test. The same test for overlap was conducted with a (j) finger whorl phenotype, expected to have no overlap with brain structure genetics, and (k) the overlap between caudate and putamen volume, expected to have very strong overlap. Overlap in the rank-ordered lists between genetic variants influencing any of the eight brain phenotypes and those creating risk for schizophrenia was not statistically significant. The overlap between hippocampal volume and presence of a whorl on the left thumb was used as a negative control and showed similar levels of overlap to brain structure and schizophrenia.