title: Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder.
abstract: 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.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: F
authors.identifier: 0000-0002-6399-9101
authors.initials: F
authors.lastname: Lescai
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: T D
authors.initials: TD
authors.lastname: Als
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Q
authors.identifier: 0000-0003-1567-2240
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: M
authors.identifier: 0000-0003-4973-8543
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Genetic Biobank of the Faroe Islands, Tórshavn, Faroe Islands.
authors.forename: G
authors.initials: G
authors.lastname: Andorsdottir
authors.affiliation: Genetic Biobank of the Faroe Islands, Tórshavn, Faroe Islands.
authors.forename: M
authors.initials: M
authors.lastname: Biskopstø
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Hedemand
authors.affiliation: Division of Psychiatry, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: Division of Psychiatry, University College London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: O'Brien
authors.affiliation: Division of Psychiatry, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Jarram
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.|BiRC-Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
authors.forename: J
authors.identifier: 0000-0003-2284-5744
authors.initials: J
authors.lastname: Grove
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Pallesen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: E
authors.identifier: 0000-0002-5358-1318
authors.initials: E
authors.lastname: Eickhardt
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.|Aarhus University Hospital, Risskov, Aarhus, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Bolund
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: D
authors.initials: D
authors.lastname: Demontis
authors.affiliation: Mental Health Centre Amager, Copenhagen, Denmark.
authors.forename: A G
authors.initials: AG
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: A
authors.initials: A
authors.lastname: McQuillin
authors.affiliation: iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.|Aarhus University Hospital, Risskov, Aarhus, Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Mors
authors.affiliation: iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.|BGI-Shenzhen, Shenzhen, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.|iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: A D
authors.initials: AD
authors.lastname: Børglum
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D003718:Denmark; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D020125:Mutation, Missense; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D000097796:Nucleolin
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C117888:PITPNM2 protein, human; C496320:NOS1 protein, human; C546621:PIK3C2A protein, human