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Bipolar, Schizophrenia GWAS Leads to Shared, Distinct Risk Variants

NEW YORK (GenomeWeb) – A large genome-wide association study has uncovered new genetic loci associated with both bipolar disorder and schizophrenia, along with disease-specific loci that seem to distinguish between the psychiatric conditions.

Members of the Psychiatric Genomics Consortium's Bipolar Disorder and Schizophrenia Working Group began by comparing genotyping profiles of 53,555 individuals with bipolar disorder or schizophrenia to those of more than 54,000 unaffected controls, uncovering 114 shared genetic contributors to the psychiatric conditions — a set enriched for variants falling in and around genes from synaptic and neuronal pathways.

"Consistent with earlier results, we found extensive genetic sharing between these two disorders, identifying 114 [genome-wide significant] loci contributing to both disorders, of which 32 are novel," corresponding author Douglas Ruderfer, a genetic medicine researcher at Vanderbilt, and colleagues wrote in a paper appearing in the current issue of Cell. "These findings point to the relevance of neuronal and synaptic biology for the shared genetic substrate of these disorders."

When the team focused on variants that differed between 23,585 individuals with schizophrenia and 15,270 bipolar disorder cases, on the other hand, it tracked down two genome-wide significant loci and other suggestive loci differentiating the conditions. Folding in further clinical insights led to polygenic risk scores corresponding to some of the 28 sub-phenotypes found within the conditions.

From these and other genetic clues, the authors suggested that bipolar disorder and schizophrenia are "neither independent nor the same," but share "particular symptom dimensions that can be captured from the genetics and used to characterize patients to ultimately inform diagnosis and treatment."

Using information at some 15.5 million directly genotyped or imputed SNPs, the team searched for variants that were over-represented in 20,129 bipolar disorder and 33,426 schizophrenia cases relative to 54,065 unaffected controls.

After accounting for linkage disequilibrium between variants, the investigators were left with 114 loci showing genome-wide significant associations with the psychiatric conditions. Their gene-based analysis of these risk variants highlighted eight pathways, including seven pathways with ties to synaptic function and/or neuronal biology.

The team took a closer look at effect sizes for variants at these risk loci in each condition with a disease-specific GWAS, before searching for distinct bipolar disorder and schizophrenia-associated loci using data for 23,585 individuals with schizophrenia and 15,270 with bipolar disorder.

The most pronounced genetic differences between the conditions turned up at sites in the DARS2 gene on chromosome 1 and near CSE1L on chromosome 20, the researchers reported, with other suggestive loci turning up on chromosomes 11, 8, and 3. They profiled such risk regions in more detail with fine mapping, brain expression data, and expression quantitative trait locus information.

Incorporating clinical data for tens of thousands of individuals affected by one of the four schizophrenia sub-phenotypes or two-dozen bipolar disorder sub-phenotypes, the investigators examined potential ties between these sub-phenotypes and polygenic risk scores stemming from each arm of the GWAS.

They saw significant links between manic schizophrenia symptoms and psychotic symptoms in bipolar disorder and a polygenic risk score developed with variants from the bipolar disorder-specific analysis, for example. And a risk score established with variants from a schizophrenia-specific analysis coincided with specific clinical features in both bipolar disorder and schizophrenia, highlighting the complex interconnections between subtypes of the two conditions.

"This work illustrates the utility of genetic data, in aggregate, at dissecting symptom heterogeneity among related disorders," the authors wrote, "and suggests that further work could aid in characterizing patients for more personalized treatment."