A meta-analysis from the Schizophrenia Working Group of the Psychiatric Genomics Consortium has revealed a large number of previously unreported genetic loci that may have a role in schizophrenia.
The aim of the Working Group was to increase the power of genome-wide association studies to detect associations with schizophrenia by combining data for all published and unpublished studies into a single meta-analysis, the results of which they have now published in Nature.
The group obtained data for a total of 36,989 cases and 113,075 controls, mostly of European ancestry, which revealed 128 single nucleotide polymorphisms across 108 linkage-disequilibrium-independent loci that were significantly associated with schizophrenia.
Statistical analysis supported a polygenic model, with multiple loci making small contributions to schizophrenia risk. Also, data from parent–offspring trios suggested that around 67%, or 176, of the loci (including those with high linkage disequilibrium) will eventually be validated – considerably more than the 30 or so previously linked to schizophrenia risk.
Of the 108 linkage-disequilibrium-independent loci identified in this analysis, 83 had not previously been linked to schizophrenia, “and therefore harbour potential new biological insights into disease aetiology”, say the researchers.
Three-quarters of the loci included protein-coding genes, with 40% containing a single gene, and a further 8% were within 20 kilobase pairs of a gene. Michael O’Donovan (Cardiff University, UK) and fellow Consortium members highlight the association with the dopamine-receptor gene DRD2, the target of antipsychotic drugs, and with a number of genes involved in neurotransmission.
In a related commentary, Jonathan Flint (University of Oxford, UK) and Marcus Munafò (University of Bristol, UK) praise the study, saying that “[f]irst and foremost, it confirms that genetics is a major cause of the illness.”
They note that the association found for DRD2 gives weight to the theory that schizophrenia may arise partly as a consequence of abnormal dopamine signalling. Also, they highlight the finding of a strong association in the major histocompatibility complex, along with associations in other areas involved with acquired immunity. “Is schizophrenia in part a disorder of acquired immunity?” they ask. “Surely this idea should start to be taken seriously.”
Finally, they discuss an association with a locus in a gene cluster known to be susceptible to smoking-related DNA changes; they suggest the finding could represent a link between smoking and schizophrenia instead of, or as well as, a direct effect of the locus on schizophrenia risk.
“As ever-larger genome-wide association studies are conducted, we will presumably begin to pick up indirect effects”, they say. “In other words, such studies may tell us about the environmental as well as the genetic causes of the disease.”
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