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Schizophrenia risk, loss of white matter integrity share genes, twin study shows

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Longitudinal imaging needed

The investigators found that white matter integrity (as indexed by fractional anisotropy) and cortical gray matter thickness were “heritable traits that were significantly reduced in people with schizophrenia,” wrote Tyrone D. Cannon, Ph.D., in an accompanying editorial. “In both cases, genetic influences shared with schizophrenia were found to account for a high proportion of these phenotypic correlations.”

But the genetic factors influencing the correlation between schizophrenia and reduced fractional anisotropy (FA) proved “independent of the genetic factors that influenced the correlation between schizophrenia and reduced cortical gray matter thickness. 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,” he wrote.

“In this case, it remains ambiguous whether reduced dendritic spine density is primary, driving some further degree of reduction in FA in tracts that link the affected pyramidal cells (i.e., beyond the reduced FA associated with schizophrenia-related susceptibility genes) or, conversely, whether disrupted white matter development leads to an additional degree of spine and synapse elimination (i.e., beyond the reductions in cortical thickness associated with schizophrenia susceptibility genes). To parse these alternatives, we need multimodal imaging data from the same high-risk individuals who are undergoing imaging on multiple occasions before the onset of illness.”

Dr. Cannon is with the departments of psychiatry and psychology at Yale University, New Haven, Conn. He reported consulting relationships with the Los Angeles County Department of Mental Health and Boehringer Ingelheim, and is listed as a coinventor on a pending patent for a biomarker for psychosis.


 

FROM JAMA PSYCHIATRY

References

Many genes that confer an increased risk for schizophrenia also underlie decreases in the integrity of white matter, according to a study of twins reported online Nov. 25 in JAMA Psychiatry.

“Global white matter integrity had a significant genetic association with schizophrenia liability, with 83.4% of the association explained by common genes,” said Marc M. Bohlken of the department of psychiatry at the University Medical Center Utrecht (The Netherlands), and his associates. “Therefore, the often reported reductions in white matter integrity [among patients with schizophrenia] can largely be explained as a genetic liability.”

The study also found that separate genetic pathways underlie white and gray matter abnormalities in patients with schizophrenia, the researchers said (JAMA Psychiatry. 2015 Nov 25. [doi: 10.1001/jamapsychiatry.2015.1925]).Patients with schizophrenia were known to have fewer of the white matter connections that efficiently transfer information among regions of the normal brain, but it was unclear whether this loss related to genetic predisposition for the disease. Therefore, the researchers used diffusion-weighted and T1-weighted imaging to study 70 individual twins whose cotwin was discordant for schizophrenia and 130 healthy individual matched control twins.

Decreased global white matter integrity, as measured by fractional anisotropy (FA), correlated phenotypically with increased risk for schizophrenia (phenotypic correlation = –0.25; 95% confidence interval, –0.38 to –0.10; P = .001), and common genes explained 83% of that link, the researchers said. “Furthermore, 8.1% of the total genetic variance in global FA was shared with genetic variance for schizophrenia liability,” they reported. Compared with controls, global FA was about 3% lower in patients with schizophrenia, and 2% lower in their monozygotic cotwins, but 0.4% higher in dizygotic cotwins, perhaps because they often were under the “liability threshold,” the investigators added. “Still, it is unlikely that this genetic correlation is entirely explained by nonadditive factors,” they added.

Half of all genetically affected brain regions involved the frontal cortex, while the rest were subcortical structures, such as the striatum and thalamus. “Decreases in white matter integrity connecting the frontal cortex with other brain regions have been suggested as a genetic marker for schizophrenia, which is consistent with our findings,” the researchers said. “Although the high connection density in frontal and subcortical regions may have influenced these findings, they are consistent with the hypothesis that impairments in frontostriatal connections are critical to the pathogenesis of schizophrenia.”

A Vidi grant from the Netherlands Organisation for Scientific Research helped fund the work. The researchers had no disclosures.

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