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GWAS Leads to Variant Linked to Schizophrenia, Bipolar Disorder

NEW YORK (GenomeWeb News) – A genome-wide association study of schizophrenia appearing online today in Nature Communications suggests that a variant in a chromosome 4 gene called NDST3 contributes to the risk of both schizophrenia and bipolar disorder.

Hebrew University of Jerusalem genetics researcher Ariel Darvasi and colleagues from Israel, the US, Germany, Japan, and Taiwan did a GWAS involving 904 Ashkenazi Jewish individuals and more than 1,600 unaffected controls from the same population.

The search led to a lone SNP in NDST3 that showed ties to both schizophrenia and bipolar disorder in follow-up experiments based on case-control samples from tens of thousands of individuals from other populations.

"Consistency of results across both schizophrenia and bipolar disorder support a growing body of evidence that current diagnostic boundaries in psychiatric nosology are not biologically valid," Darvasi and co-authors concluded.

"Although modifier genes influencing specific clinical features of the phenotype may be identified by future research," they wrote, "NDST3 variation appears to predispose to severe psychiatric disease of varying presentations."

Although much of the heritability for schizophrenia and bipolar disease remains undefined, the researchers noted, there have been hints from past genetic and epidemiological studies that risk factors for the two conditions overlap, at least to some extent.

To explore potential relationships between the diseases, the group opted to focus on Ashkenazi Jewish individuals, reasoning that this founder population might show more pronounced risk allele associations.

To that end, researchers used Illumina Human Omni1-Quad arrays to genotype thousands of schizophrenia cases and controls from the Ashkenazi Jewish population. After tossing out samples with low-quality data, they were left with SNP profiles for 904 individuals with schizophrenia and 1,650 without.

A search for variants over-represented in those with schizophrenia led to a handful of SNPs with apparent genome-wide significant ties to the condition, though the association was most pronounced for a single chromosome 4 SNP.

The team went on to test that variant, which falls in an intergenic portion of the NDST3 gene, in almost a dozen more case-control cohorts representing 23,191 unaffected controls and individuals with either schizophrenia or bipolar disease.

Results from those cohorts confirmed the NDST3 variant's association with schizophrenia. But researchers also found significant links to bipolar disorder risk.

And because NDST3 codes for an enzyme that influences heparan sulphate binding — a process that's been implicated in brain-related processes such as axon formation and neurite outgrowth — the team decided to explore the possibility that the newly detected risk variant might mediate NDST3 expression in some manner.

Indeed, when they used arrays to assess gene expression patterns in post-mortem brain samples from 39 individuals with schizophrenia, 36 individuals with bipolar disorder, and 44 unaffected controls, researchers saw that those with the schizophrenia and bipolar disorder-associated alleles also tended to have enhanced NDST3 expression in the cerebellum region of their brains.

Together with transcript expression profiles from dozens of human, rat, and macaque brain samples, the study's authors argued that such findings point to a potential regulatory role for the risk SNP.