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...
Published in: | Translational Psychiatry |
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Online Access: | https://curis.ku.dk/portal/da/publications/wholeexome-sequencing-of-individuals-from-an-isolated-population-implicates-rare-risk-variants-in-bipolar-disorder(e062f1d3-cbd6-4dc2-a1de-3cdca39199ed).html https://doi.org/10.1038/tp.2017.3 https://curis.ku.dk/ws/files/196168109/tp20173.pdf |
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ftcopenhagenunip:oai:pure.atira.dk:publications/e062f1d3-cbd6-4dc2-a1de-3cdca39199ed 2024-05-19T07:40:03+00:00 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 2017 application/pdf https://curis.ku.dk/portal/da/publications/wholeexome-sequencing-of-individuals-from-an-isolated-population-implicates-rare-risk-variants-in-bipolar-disorder(e062f1d3-cbd6-4dc2-a1de-3cdca39199ed).html https://doi.org/10.1038/tp.2017.3 https://curis.ku.dk/ws/files/196168109/tp20173.pdf eng eng info:eu-repo/semantics/openAccess 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 2017 , ' Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder ' , Translational Psychiatry , vol. 7 , e1034 . https://doi.org/10.1038/tp.2017.3 Bipolar Disorder/genetics Calcium-Binding Proteins/genetics Case-Control Studies Denmark Gene Regulatory Networks Genetic Predisposition to Disease Humans Membrane Proteins/genetics Mutation Missense Nitric Oxide Synthase Type I/genetics Phosphatidylinositol 3-Kinases/genetics Phosphoproteins/genetics Polymorphism Genetic RNA-Binding Proteins/genetics Sequence Analysis DNA United Kingdom article 2017 ftcopenhagenunip https://doi.org/10.1038/tp.2017.3 2024-04-25T00:45:04Z 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. Article in Journal/Newspaper Faroe Islands University of Copenhagen: Research Translational Psychiatry 7 2 e1034 e1034 |
institution |
Open Polar |
collection |
University of Copenhagen: Research |
op_collection_id |
ftcopenhagenunip |
language |
English |
topic |
Bipolar Disorder/genetics Calcium-Binding Proteins/genetics Case-Control Studies Denmark Gene Regulatory Networks Genetic Predisposition to Disease Humans Membrane Proteins/genetics Mutation Missense Nitric Oxide Synthase Type I/genetics Phosphatidylinositol 3-Kinases/genetics Phosphoproteins/genetics Polymorphism Genetic RNA-Binding Proteins/genetics Sequence Analysis DNA United Kingdom |
spellingShingle |
Bipolar Disorder/genetics Calcium-Binding Proteins/genetics Case-Control Studies Denmark Gene Regulatory Networks Genetic Predisposition to Disease Humans Membrane Proteins/genetics Mutation Missense Nitric Oxide Synthase Type I/genetics Phosphatidylinositol 3-Kinases/genetics Phosphoproteins/genetics Polymorphism Genetic RNA-Binding Proteins/genetics Sequence Analysis DNA United Kingdom 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 |
topic_facet |
Bipolar Disorder/genetics Calcium-Binding Proteins/genetics Case-Control Studies Denmark Gene Regulatory Networks Genetic Predisposition to Disease Humans Membrane Proteins/genetics Mutation Missense Nitric Oxide Synthase Type I/genetics Phosphatidylinositol 3-Kinases/genetics Phosphoproteins/genetics Polymorphism Genetic RNA-Binding Proteins/genetics Sequence Analysis DNA United Kingdom |
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. |
format |
Article in Journal/Newspaper |
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 |
title |
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_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_sort |
whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder |
publishDate |
2017 |
url |
https://curis.ku.dk/portal/da/publications/wholeexome-sequencing-of-individuals-from-an-isolated-population-implicates-rare-risk-variants-in-bipolar-disorder(e062f1d3-cbd6-4dc2-a1de-3cdca39199ed).html https://doi.org/10.1038/tp.2017.3 https://curis.ku.dk/ws/files/196168109/tp20173.pdf |
genre |
Faroe Islands |
genre_facet |
Faroe Islands |
op_source |
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 2017 , ' Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder ' , Translational Psychiatry , vol. 7 , e1034 . https://doi.org/10.1038/tp.2017.3 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1038/tp.2017.3 |
container_title |
Translational Psychiatry |
container_volume |
7 |
container_issue |
2 |
container_start_page |
e1034 |
op_container_end_page |
e1034 |
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1799479632390520832 |