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White matter integrity could indicate genetic risk for schizophrenia

Independent genetic pathways lead to gray and white matter abnormalities in schizophrenia, suggesting white matter integrity as a potential primary phenotype linking genes to biological pathways associated with risk for schizophrenia.

“Several studies have found that white matter is affected not only in patients with schizophrenia but also in individuals at increased risk for the disease; however, other studies did not find significant differences between individuals at increased risk and healthy control participants,” Marc M. Bohlken, MSc, of University Medical Center Utrecht, the Netherlands, and colleagues wrote. “The areas of white matter that are reduced in individuals at increased risk overlap with those found to be affected in patients, suggesting that familial, and possibly genetic, factors contribute to this effect.”

To assess whether white matter integrity is associated with genetic risk for schizophrenia, researchers measured structural connectivity and network efficiency via diffusion-weighted imaging to determine fractional anisotropy in 70 individual twins discordant for schizophrenia and 130 matched individual health control twins. The study cohort included 30 monozygotic twins and 40 dizygotic twins.

Researchers found a significant correlation between lower global fractional anisotropy and increased schizophrenia risk (P = .001), with 83.4% explained by common genes.

Overall, 8.1% of genetic variation in global fractional anisotropy was shared with genetic variance in schizophrenia risk.

Reductions in network connectivity — defined by researchers as fractional anisotropy-weighted local efficiency — in frontal, striatal and thalamic regions included 85.7% of genetically affected areas.

Global fractional anisotropy contributed to schizophrenia risk independent of other genetic markers, such as white matter volume and cortical thickness, according to multivariate genetic modeling.

“Although reduced [fractional anisotropy] and reduced cortical thickness are correlated with each other in patients with schizophrenia, according to the results of Bohlken et al, this is not because of shared genetic causes. Thus, their phenotypic correlation in schizophrenia may reflect an additional degree of effect over and above that associated with their respective inherited substrates, as in a secondary effect,” Tyrone D. Cannon, PhD, of Yale University, New Haven, Connecticut, wrote in an accompanying editorial. “In this case, it remains ambiguous whether reduced dendritic spine density is primary, driving some further degree of reduction in [fractional anisotropy] in tracts that link the affected pyramidal cells (ie, beyond the reduced [fractional anisotropy] associated with schizophrenia-related susceptibility genes) or, conversely, whether disrupted white matter development leads to an additional degree of spine and synapse elimination (ie, beyond the reductions in cortical thickness associated with schizophrenia susceptibility genes).” – by Amanda Oldt

Disclosure: Bohlken and colleagues report no relevant financial disclosures. Cannon reports working as a consultant to the Los Angeles County Department of Mental Health and Boehringer Ingelheim Pharmaceuticals; and is a coinventor on a pending patent for a blood-based predictive biomarker for psychosis. Please see the full study for a list of all authors’ relevant financial disclosures.