Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- Surendran, Praveen, Feofanova, Elena, Lahrouchi, Najim, Ntalla, Ionna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi, Cartwright, James, Hellwege, Jacklyn, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang, Prins, Bram, Stewart, Isobel, Cabrera, Claude, Eales, James, Akbarov, Artur, Auer, Paul, Charchar, Fadi, Howson, Joanna, LifeLines Cohort, Study, Epic, C. V. D., Epic InterAct, Understanding Society Scientific, Group, Million Veteran, Program
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
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- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
- Full Text:
- Reviewed:
- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
- Bonnelykke, Klaus, Matheson, Melanie, Pers, Tune, Granell, Raquel, Strachan, David, Couto Alves, Alexessander, Linneberg, Allan, Curtin, John, Warrington, Nicole, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Moller, Eskil, Simpson, Angela, Pourcain, Beate, Coin, Lachlan, Hui, Jennie, Walters, Eugene, Tiesler, Carla, Duffy, David, Jones, Graham, Marks, Guy, Danoy, Patrick, Meszaros, Desiree, Hayden, Catherine, Henders, Anjali, Chapman, Brett, Kemp, Andrew, Cheah, Faang, Southey, Melissa, Roberts, Mary, Tovey, Euan, Giles, Graham, Chung, Li, Thomas, Paul, Feather, Ian, Temple, Suzanna, Beilby, John, Morrison, Stephen, Johns, David, Mitrpant, Chalermchai, Shelton, Brad, Jenkins, Mark, Britton, Warwick, Le Souef, Peter, Hopper, John, Leeder, Stephen, Musk, Bill, Martin, Nicholas, Brown, Matthew, Ring, Susan, McArdle, Wendy, Price, Loren, Robertson, Colin, Pekkanen, Juha, Tang, Clara, Thiering, Elisabeth, Montgomery, Grant, Hartikainen, Anna-Liisa, Dharmage, Shyamali, Husemoen, Lise, Herder, Christian, Kemp, John, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael, Fairfax, Benjamin, Knight, Julian, Gupta, Ramneek, Thompson, Philip, Holt, Patrick, Sly, Peter, Hirschhorn, Joel, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje, Custovic, Adnan, Pennell, Craig, Jarvelin, Marjo-Riitta, Koppelman, Gerard, Timpson, Nicholas, Ferreira, Manuel, Bisgaard, Hans, Henderson, A. John
- Authors: Bonnelykke, Klaus , Matheson, Melanie , Pers, Tune , Granell, Raquel , Strachan, David , Couto Alves, Alexessander , Linneberg, Allan , Curtin, John , Warrington, Nicole , Standl, Marie , Kerkhof, Marjan , Jonsdottir, Ingileif , Bukvic, Blazenka , Kaakinen, Marika , Sleimann, Patrick , Thorleifsson, Gudmar , Thorsteinsdottir, Unnur , Schramm, Katharina , Baltic, Svetlana , Kreiner-Moller, Eskil , Simpson, Angela , Pourcain, Beate , Coin, Lachlan , Hui, Jennie , Walters, Eugene , Tiesler, Carla , Duffy, David , Jones, Graham , Marks, Guy , Danoy, Patrick , Meszaros, Desiree , Hayden, Catherine , Henders, Anjali , Chapman, Brett , Kemp, Andrew , Cheah, Faang , Southey, Melissa , Roberts, Mary , Tovey, Euan , Giles, Graham , Chung, Li , Thomas, Paul , Feather, Ian , Temple, Suzanna , Beilby, John , Morrison, Stephen , Johns, David , Mitrpant, Chalermchai , Shelton, Brad , Jenkins, Mark , Britton, Warwick , Le Souef, Peter , Hopper, John , Leeder, Stephen , Musk, Bill , Martin, Nicholas , Brown, Matthew , Ring, Susan , McArdle, Wendy , Price, Loren , Robertson, Colin , Pekkanen, Juha , Tang, Clara , Thiering, Elisabeth , Montgomery, Grant , Hartikainen, Anna-Liisa , Dharmage, Shyamali , Husemoen, Lise , Herder, Christian , Kemp, John , Elliot, Paul , James, Alan , Waldenberger, Melanie , Abramson, Michael , Fairfax, Benjamin , Knight, Julian , Gupta, Ramneek , Thompson, Philip , Holt, Patrick , Sly, Peter , Hirschhorn, Joel , Blekic, Mario , Weidinger, Stephan , Hakonarsson, Hakon , Stefansson, Kari , Heinrich, Joachim , Postma, Dirkje , Custovic, Adnan , Pennell, Craig , Jarvelin, Marjo-Riitta , Koppelman, Gerard , Timpson, Nicholas , Ferreira, Manuel , Bisgaard, Hans , Henderson, A. John
- Date: 2013
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 45, no. 8 (2013), p. 902-906
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- Description: Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
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