About the study

Only few whole genome or whole exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of small and isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed up in a British sample of 2,025 cases and 1,358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from GWAS data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test).

A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus.

Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

The article “Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder” was published in Translational Psychiatry (2017) 7, e1034; doi:10.1038/tp.2017.3

Facts about the study

• Isolated populations can be an effective strategy to study complex traits with a high heritability
• NOS1 is implicated in Bipolar Disorder, and the finding is intriguing because it acts as the second messenger of the N-methyl-D-aspartate receptor and interacts with both the dopaminergic as well as the serotonergic system;
• A missense variant in PITPNM2 has only been seen in the Faroese population, but is located in a highly significant schizophrenia GWAS locus that harbours multiple genes.

Further information

Francesco Lescai, Department of Biomedicine Aarhus University lescai@biomed.au.dk

Anders Børglum, Department of Biomedicine Aarhus University anders@biomed.au.dk