White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis

Bipolar and psychotic disorders are highly heritable and associated with widespread white matter microstructure abnormalities. In this project, we compare white matter microstructure of unaffected first-degree relatives of individuals with bipolar disorder (FDR-BD) or psychotic disorder (FDR-SZ) to that of control participants. As secondary, exploratory aims, we examined the associations of childhood traumatic experiences and working memory with white matter microstructure across relatives and controls. Finally, we compared participants with BD or SZ to controls. We combined 11 samples from 9 institutions with 408 FDR-BD, 542 FDR-SZ, 841 controls, 255 BD and 464 SZ. Analysis of the diffusion-weighted imaging data followed the ENIGMA pipeline protocols, resulting in mean fractional anisotropy (FA). Sample-level analyses were linear mixed-effects models with group as the main predictor, adjusting for age and sex and correcting for dependence between family members. Samples were combined using random-effects meta-analysis. FDR-BD showed higher FA in the posterior limb of the internal capsule (PLIC) than controls. FDR-SZ did not demonstrate any FA differences from controls. Participants with BD or SZ diagnoses from the same samples did show the expected lower FA than controls in several tracts. Working memory scores were more positively related to FA in the PLIC in FDR-SZ than in controls. The level of childhood traumatic experiences was not related to FA. White matter deficits observed in people with SZ and BD were not detected in FDR-BD and FDR-SZ, suggesting that these findings in patients are not due to familial risk but may pertain to illness itself.