TY - JOUR

T1 - Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

AU - Lescai, F

AU - Als, T D

AU - Li, Q

AU - Nyegaard, M

AU - Andorsdottir, G

AU - Biskopstø, M

AU - Hedemand, A

AU - Fiorentino, A

AU - O'Brien, N

AU - Jarram, A

AU - Liang, J

AU - Grove, J

AU - Pallesen, J

AU - Eickhardt, E

AU - Mattheisen, M

AU - Bolund, L

AU - Demontis, D

AU - Wang, A G

AU - McQuillin, A

AU - Mors, O

AU - Wang, J

AU - Børglum, A D

PY - 2017

Y1 - 2017

N2 - Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. 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 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 2025 cases and 1358 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 genome-wide association studies (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.

AB - Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. 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 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 2025 cases and 1358 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 genome-wide association studies (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.

KW - Bipolar Disorder/genetics

KW - Calcium-Binding Proteins/genetics

KW - Case-Control Studies

KW - Denmark

KW - Gene Regulatory Networks

KW - Genetic Predisposition to Disease

KW - Humans

KW - Membrane Proteins/genetics

KW - Mutation, Missense

KW - Nitric Oxide Synthase Type I/genetics

KW - Phosphatidylinositol 3-Kinases/genetics

KW - Phosphoproteins/genetics

KW - Polymorphism, Genetic

KW - RNA-Binding Proteins/genetics

KW - Sequence Analysis, DNA

KW - United Kingdom

U2 - 10.1038/tp.2017.3

DO - 10.1038/tp.2017.3

M3 - Journal article

C2 - 28195573

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - e1034

ER -