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

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 population...

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Autores principales: Lescai, F, Als, T D, Li, Q, Nyegaard, M, Andorsdottir, G, Biskopstø, M, Hedemand, A, Fiorentino, A, O'Brien, N, Jarram, A, Liang, J, Grove, J, Pallesen, J, Eickhardt, E, Mattheisen, M, Bolund, L, Demontis, D, Wang, A G, McQuillin, A, Mors, O, Wang, J, Børglum, A D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438033/
https://www.ncbi.nlm.nih.gov/pubmed/28195573
http://dx.doi.org/10.1038/tp.2017.3
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author Lescai, F
Als, T D
Li, Q
Nyegaard, M
Andorsdottir, G
Biskopstø, M
Hedemand, A
Fiorentino, A
O'Brien, N
Jarram, A
Liang, J
Grove, J
Pallesen, J
Eickhardt, E
Mattheisen, M
Bolund, L
Demontis, D
Wang, A G
McQuillin, A
Mors, O
Wang, J
Børglum, A D
author_facet Lescai, F
Als, T D
Li, Q
Nyegaard, M
Andorsdottir, G
Biskopstø, M
Hedemand, A
Fiorentino, A
O'Brien, N
Jarram, A
Liang, J
Grove, J
Pallesen, J
Eickhardt, E
Mattheisen, M
Bolund, L
Demontis, D
Wang, A G
McQuillin, A
Mors, O
Wang, J
Børglum, A D
author_sort Lescai, F
collection PubMed
description 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.
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spelling pubmed-54380332017-06-01 Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder Lescai, F Als, T D Li, Q Nyegaard, M Andorsdottir, G Biskopstø, M Hedemand, A Fiorentino, A O'Brien, N Jarram, A Liang, J Grove, J Pallesen, J Eickhardt, E Mattheisen, M Bolund, L Demontis, D Wang, A G McQuillin, A Mors, O Wang, J Børglum, A D Transl Psychiatry Original Article 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. Nature Publishing Group 2017-02 2017-02-14 /pmc/articles/PMC5438033/ /pubmed/28195573 http://dx.doi.org/10.1038/tp.2017.3 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Lescai, F
Als, T D
Li, Q
Nyegaard, M
Andorsdottir, G
Biskopstø, M
Hedemand, A
Fiorentino, A
O'Brien, N
Jarram, A
Liang, J
Grove, J
Pallesen, J
Eickhardt, E
Mattheisen, M
Bolund, L
Demontis, D
Wang, A G
McQuillin, A
Mors, O
Wang, J
Børglum, A D
Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title_full Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title_fullStr Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title_full_unstemmed Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title_short Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
title_sort whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438033/
https://www.ncbi.nlm.nih.gov/pubmed/28195573
http://dx.doi.org/10.1038/tp.2017.3
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