Genetic Variants Tied to Both Brain Morphology and Schizophrenia Risk

By David Douglas

July 06, 2021

NEW YORK (Reuters Health) - Most genetic variants associated with cortical surface area and thickness are also linked to the risk of developing schizophrenia, a new study shows.

"Neuroimaging studies have identified cortical structural alterations in schizophrenia, and large genome-wide association studies have identified hundreds of genetic variants associated with the disorder, and brain structure phenotypes," said As Dr. Ole A. Andreassen of Oslo University Hospital Ullevaal, in Norway.

"However, previous studies using standard analytical tools have not been able to identify the shared genetic risk between schizophrenia and cortical morphology and the related molecular genetic mechanisms remain unknown," he told Reuters Health by email.

Dr. Andreassen and colleagues examined independent genome-wide-association-study data on schizophrenia from more than 105,000 individuals and on brain cortical surface area (SA) and thickness (TH) from more than 33,000 individuals. They used MiXeR, a statistical tool that quantifies polygenic overlap irrespective of genetic correlation as well as conditional/conjunctional false-discovery rate (cFDR) analysis.

MiXeR estimated schizophrenia to be more polygenic than total SA and average TH (9,703 single-nucleotide variants, or SNVs, vs. 2101 and 1,363, respectively).

Most of the SNVs associated with total SA (93.6%) "may be associated with the development of schizophrenia," the researchers report. This was the case for 97.0% of the SNVs associated with average TH. Subsequent cFDR analysis identified 44 schizophrenia risk loci shared with total SA and 23 shared with average TH.

These results, said Dr. Andreassen, "suggest that the majority of genetic variants of cortical structure (surface area and cortical thickness) also contribute to schizophrenia disease risk, providing an insight into the molecular mechanisms underlying the well-established phenotypical correlation. Further studies are warranted to determine the biological mechanisms involved in cortical structural alternations and their impact on the pathogenesis of schizophrenia."

"Meanwhile," he concluded, "the current findings provide evidence that genetic factors influencing brain cortical structure are also associated with the development of schizophrenia, implicating brain variation in schizophrenia disease mechanisms. Further, the current findings can form the basis of developing precision medicine approaches in psychiatry, combining brain imaging and genetics risk factors."

SOURCE: JAMA Psychiatry, online June 23, 2021.