Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure

Abstract

Background: Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development.

Methods: In a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability.

Results: In total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%).

Conclusions: Intellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ.

Keywords: IQ; MRI; cortex; heritability; schizophrenia; white matter.

Fig. 1.

Multivariate model representation. Rectangular boxes represent the observed variables: cortical surface (CS), intelligence quotient (IQ), fractional anisotropy (FA), cortical thickness (CT) and schizophrenia liability (SZ). Circles in shades of red represent latent genetic factors, the arrows (a₁₁…a₅₅) represent the genetic factor loadings on the observed variables. Circles in shades of blue represent the latent unique environmental factors, the arrows (e₁₁…e₅₅) represent the factor loadings on the observed variables. The green circle represents the latent common environmental factor loading on SZ. The heritability of SZ was fixed, thus squared factor loadings $a_{15}^2\dots a_{55}^2$ add up to 81%. Squared factor loadings $e_{15}^2\dots e_{55}^2$ add up to 8% and $c_{55}^2$ was constrained at 11%. Fat arrows indicate significant paths, dashed arrows represent paths that were not significant. The numbers next to the paths represent the factor loadings.