medwireNews: A large study in JAMA Psychiatry has confirmed the association of several genetic variants with schizophrenia susceptibility and identified several molecular pathways that could be involved.
Researchers led by Edwin van den Oord (Virginia Commonwealth University, Richmond, USA) identified single nucleotide polymorphisms (SNPs) of interest from a meta-analysis of 18 genome-wide association studies, and from six databases. They then tested the associations of these SNPs with schizophrenia in 6298 people from 1811 nuclear families that included at least one person with schizophrenia.
Of the SNPs that remained associated with schizophrenia in the replication cohort, 89% had the same direction of effect as in the meta-analysis. The meta-analysis consisted only of people of European ancestry; among the 2740 people in the replication cohort who were of European ancestry, 93% of the SNPs had the same direction of effect. There were 23 of these, but having one of these mutations altered people's odds for having schizophrenia only by about 20%, which the team says "confirms the polygenetic nature" of schizophrenia.
A notable new finding was that a SNP in the gene BCL2 was associated with schizophrenia. BCL2 is thought to be involved with neuronal differentiation, and reduced levels have been reported in patients with schizophrenia.
In a related editorial, John Hardy (UCL Institute of Neurology, London, UK) says the study provides convincing evidence for a genetic component to schizophrenia risk. But he cautions: "Each of the loci provisionally identified has a very small effect size, and even together, they explain a tiny proportion of the familiality of the disease."
The replication cohort also included 1262 people of African heritage and 2296 of Asian ancestry. Associations between schizophrenia and SNPs in genes that were not in the major histocompatibility complex (MHC) region replicated with similar strength in all three ethnic groups. However, associations with SNPs in the MHC region (in genes NEB, NOTCH4, C10orf32, AS3MT, CNNM2, NT5C2, MKL1) replicated only in people of European ancestry. These SNPs were also in linkage disequilibrium in the European group, reflecting the "evolutionary significance" of the SNPs, say the researchers.
On grouping SNPs by biologic pathway, the team found that several pathways involved with neuronal and immune function were associated with schizophrenia. The strongest association was for SNPs associated with axon guidance.
Hardy believes that rarer but higher-risk mutations may emerge over time, but says: "However, it seems certain that much of the familial clustering will remain unexplained by genetic analysis and will eventually be assigned to shared experience of affected individuals. Perhaps the fact that the loci confirmed in this study include those encoding proteins involved in the plasticity of the nervous system point to this conclusion already."
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