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Schizophrenia Study IDs New Risk Loci, Characterizes Common Variant Role

NEW YORK (GenomeWeb) – The slew of common genetic variants implicated in schizophrenia appear to mark regions of the genome under particularly pronounced selective pressure as well as genes that are sensitive to mutation, according to new research from an international team led by investigators in the UK and elsewhere.

Through a genome-wide association study and meta-analysis involving nearly 11,300 individuals with schizophrenia and more than 24,500 without, the researchers narrowed in on 145 common variant-based risk loci for schizophrenia — a set that included 50 loci not linked to schizophrenia in the past.

When the team delved into the nature of these associations, it uncovered potential causal genes at nearly three-dozen of the schizophrenia-linked loci using a combination of fine mapping, available brain gene expression profiles, and chromosome conformation data. The results, published online yesterday in Nature Genetics, suggested that common schizophrenia-associated variants often fall in loss-of-function (LoF) intolerant genes from parts of the genome with strong background selection.

"Given that mutation intolerance is due to high selection pressure, our finding that schizophrenia risk variants that persist at common allele frequencies are enriched in LoF-intolerant genes might appear counterintuitive. However, new evidence presented here suggests that this can be reconciled by [background selection], which is a consequence of purifying selection in regions of low recombination," co-corresponding authors and Cardiff University neuropsychiatric genetics and genomics researchers James Walters, Michael O'Donovan, and Michael Owen and their colleagues wrote.

While a wide range of common to rarer variants have been implicated in schizophrenia susceptibility and heritability, the team noted that the "relative contributions of alleles of various frequencies are not fully resolved." Moreover, it is unclear how common variants linked to the polygenic condition have managed to stick around at relatively high frequencies in the broader population.

The researchers initially brought together genome-wide genotyping information for 11,260 individuals with schizophrenia and 24,542 unaffected controls profiled for a prior study in the UK, by study collaborators, or in public databases. The set included more than 5,200 cases and 18,800 controls beyond those considered for a prior GWAS, they noted.

The team included data for thousands more individuals profiled by the Psychiatric Genomics Consortium for a subsequent meta-analysis, which included 40,675 cases and 64,643 controls, leading to 179 SNPs at 145 genomic loci that appeared to have genome-wide significant ties to schizophrenia.

Focusing on 50 loci not found in previous schizophrenia studies, the researchers tested another 5,662 individuals with schizophrenia and 154,224 without, verifying 43 of the new associations.

They subsequently brought together a wide swath of expression, exome sequence, copy number, chromatin conformation, gene function, and other data to fine map the associations and get a glimpse at the genes and sequences overlapping with the new and previously known schizophrenia-associated variants in a systems-based analysis.

Along with over-representation of loss-of-function (LoF) mutation-intolerant genes and background selection, the team narrowed in on half a dozen sets of schizophrenia-related genes, including hundreds of genes implicated in electrical activity in the nervous system and more than 1,900 genes linked to a more amorphous "abnormal behavior" phenotype.

"Our study provides the first evidence linking common variation in LoF-intolerant genes to the risk of developing schizophrenia and demonstrates that these genes account for a substantial proportion (30 percent) of the SNP-based heritability of schizophrenia," the authors explained. "Systems genomics analysis highlights six gene sets that are independently associated with schizophrenia and point to molecular, physiological, and behavioral pathways involved in schizophrenia pathogenesis."