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Schizophrenia Exome Sequencing Study in South African Population Reveals Rare Mutations, Pathways

NEW YORK – An international team from the US and South Africa has characterized genetic contributors to schizophrenia in the Xhosa population from South Africa, identifying rare variants in brain-related pathways that overlap with those described in other populations.

While the rates of schizophrenia among the Xhosa are on par with those in other human populations, the researchers explained, the work provided an opportunity to dig into the genetics of this condition in an ancestral African population, which harbors more genetic variation than non-African populations.

For their study, published in Science on Thursday, the researchers searched for common and rare contributors to schizophrenia, comparing exome sequences for more than 900 Xhosa individuals with schizophrenia to those from controls matched for age, gender, education, and location. Among other distinct genetic features in the schizophrenia cases, they highlighted an uptick in rare or private damaging mutations in genes, in particular synaptic genes, in affected individuals — consistent with findings previously reported in other populations.

"In both African and non-African populations, a causal role for private damaging mutations in genes that are important to brain development is consistent with the nature of schizophrenia and with selection against it," co-senior and corresponding author Mary-Claire King, a researcher at the University of Washington, and her colleagues wrote.

Past work indicates that South Africa's Xhosa population — which is particularly prominent in the country's Eastern Cape region — belongs to a Bantu-speaking lineage that migrated from eastern to southern Africa hundreds of years ago and subsequently mixed with individuals from the early-diverging San lineage, the team explained. Given the genetic diversity in Africa, the investigators reasoned that a genetic study of schizophrenia in the Xhosa would complement and expand prior analyses focused on individuals from European or Asian populations.

"The study was undertaken not because the Xhosa have an unusual prevalence of schizophrenia," the authors explained, "but because African populations harbor the greatest wealth of human genetic diversity."

The researchers enrolled nearly 2,100 self-identified Xhosa participants, focusing on more than 1,800 individuals who consented to exome sequencing for the genetic analysis presented in the paper. That group included 909 schizophrenia cases recruited at inpatient psychiatric centers as well as outpatient clinics, they noted, along with 919 carefully matched controls.

For a rare variant-focused analysis, the team looked for private nonsense, frameshift, splice site disrupting, or predicted damaging missense mutations in mutation-intolerant genes, tallying the genes impacted by such alterations in both the cases and the control individuals. The search suggested that rare, damaging mutations were more common in individuals with schizophrenia, for example, often falling in brain-expressed genes or genes such as GRUA2, CACNA1A, or CNTNAP1 in synaptic activity-related pathways ranging from calcium channel signaling to cell adhesion.

Those results were backed up by available post-mortem brain tissue expression profiles from individuals with schizophrenia and other neurodevelopmental conditions, the researchers reported. In addition, the overabundance of private damaging mutations detected in the Xhosa schizophrenia patients appeared to hold in a subsequent analysis of schizophrenia cases and controls in Sweden, albeit with a smaller effect size.

"Results from African and European cohorts converge, both implicating disruptions in synaptic architecture and plasticity," the authors wrote, noting that "[i]nterventions designed to remediate disruption in synaptic structural organization and intracellular signaling pathways potentially offer more specific therapeutic benefits [than conventional antipsychotic medications]." 

In an interview this week, King noted that the team plans to enroll at least twice as many individuals for the next round of the study. Those participants will undergo whole-genome sequencing, allowing the researchers to study copy number variants and non-coding variants. Also, a subset of participants for whom cell lines are available will likely be sequenced with Pacific Biosciences long-read sequencing technology, she said.

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