%0 Journal Article %J BMC Genomics %D 2022 %T Rare coding variants in RCN3 are associated with blood pressure. %A He, Karen Y %A Kelly, Tanika N %A Wang, Heming %A Liang, Jingjing %A Zhu, Luke %A Cade, Brian E %A Assimes, Themistocles L %A Becker, Lewis C %A Beitelshees, Amber L %A Bielak, Lawrence F %A Bress, Adam P %A Brody, Jennifer A %A Chang, Yen-Pei Christy %A Chang, Yi-Cheng %A de Vries, Paul S %A Duggirala, Ravindranath %A Fox, Ervin R %A Franceschini, Nora %A Furniss, Anna L %A Gao, Yan %A Guo, Xiuqing %A Haessler, Jeffrey %A Hung, Yi-Jen %A Hwang, Shih-Jen %A Irvin, Marguerite Ryan %A Kalyani, Rita R %A Liu, Ching-Ti %A Liu, Chunyu %A Martin, Lisa Warsinger %A Montasser, May E %A Muntner, Paul M %A Mwasongwe, Stanford %A Naseri, Take %A Palmas, Walter %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Sheu, Wayne H-H %A Shimbo, Daichi %A Smith, Jennifer A %A Snively, Beverly M %A Yanek, Lisa R %A Zhao, Wei %A Blangero, John %A Eric Boerwinkle %A Chen, Yii-Der Ida %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Fornage, Myriam %A He, Jiang %A Hou, Lifang %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear E %A Kooperberg, Charles %A Lloyd-Jones, Donald %A Loos, Ruth J F %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A North, Kari E %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Rao, D C %A Redline, Susan %A Reiner, Alex P %A Rich, Stephen S %A Rotter, Jerome I %A Taylor, Kent D %A Tracy, Russell %A Vasan, Ramachandran S %A Morrison, Alanna C %A Levy, Daniel %A Chakravarti, Aravinda %A Arnett, Donna K %A Zhu, Xiaofeng %K Blood Pressure %K Genetic Linkage %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Precision Medicine %K Whole Genome Sequencing %X

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.

RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10).

CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

%B BMC Genomics %V 23 %P 148 %8 2022 Feb 19 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35183128?dopt=Abstract %R 10.1186/s12864-022-08356-4 %0 Journal Article %J Mol Psychiatry %D 2021 %T Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. %A Wang, Heming %A Noordam, Raymond %A Cade, Brian E %A Schwander, Karen %A Winkler, Thomas W %A Lee, Jiwon %A Sung, Yun Ju %A Bentley, Amy R %A Manning, Alisa K %A Aschard, Hugues %A Kilpeläinen, Tuomas O %A Ilkov, Marjan %A Brown, Michael R %A Horimoto, Andrea R %A Richard, Melissa %A Bartz, Traci M %A Vojinovic, Dina %A Lim, Elise %A Nierenberg, Jovia L %A Liu, Yongmei %A Chitrala, Kumaraswamynaidu %A Rankinen, Tuomo %A Musani, Solomon K %A Franceschini, Nora %A Rauramaa, Rainer %A Alver, Maris %A Zee, Phyllis C %A Harris, Sarah E %A van der Most, Peter J %A Nolte, Ilja M %A Munroe, Patricia B %A Palmer, Nicholette D %A Kühnel, Brigitte %A Weiss, Stefan %A Wen, Wanqing %A Hall, Kelly A %A Lyytikäinen, Leo-Pekka %A O'Connell, Jeff %A Eiriksdottir, Gudny %A Launer, Lenore J %A de Vries, Paul S %A Arking, Dan E %A Chen, Han %A Eric Boerwinkle %A Krieger, Jose E %A Schreiner, Pamela J %A Sidney, Stephen %A Shikany, James M %A Rice, Kenneth %A Chen, Yii-Der Ida %A Gharib, Sina A %A Bis, Joshua C %A Luik, Annemarie I %A Ikram, M Arfan %A Uitterlinden, André G %A Amin, Najaf %A Xu, Hanfei %A Levy, Daniel %A He, Jiang %A Lohman, Kurt K %A Zonderman, Alan B %A Rice, Treva K %A Sims, Mario %A Wilson, Gregory %A Sofer, Tamar %A Rich, Stephen S %A Palmas, Walter %A Yao, Jie %A Guo, Xiuqing %A Rotter, Jerome I %A Biermasz, Nienke R %A Mook-Kanamori, Dennis O %A Martin, Lisa W %A Barac, Ana %A Wallace, Robert B %A Gottlieb, Daniel J %A Komulainen, Pirjo %A Heikkinen, Sami %A Mägi, Reedik %A Milani, Lili %A Metspalu, Andres %A Starr, John M %A Milaneschi, Yuri %A Waken, R J %A Gao, Chuan %A Waldenberger, Melanie %A Peters, Annette %A Strauch, Konstantin %A Meitinger, Thomas %A Roenneberg, Till %A Völker, Uwe %A Dörr, Marcus %A Shu, Xiao-Ou %A Mukherjee, Sutapa %A Hillman, David R %A Kähönen, Mika %A Wagenknecht, Lynne E %A Gieger, Christian %A Grabe, Hans J %A Zheng, Wei %A Palmer, Lyle J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Morrison, Alanna C %A Pereira, Alexandre C %A Fornage, Myriam %A Psaty, Bruce M %A van Duijn, Cornelia M %A Liu, Ching-Ti %A Kelly, Tanika N %A Evans, Michele K %A Bouchard, Claude %A Fox, Ervin R %A Kooperberg, Charles %A Zhu, Xiaofeng %A Lakka, Timo A %A Esko, Tõnu %A North, Kari E %A Deary, Ian J %A Snieder, Harold %A Penninx, Brenda W J H %A Gauderman, W James %A Rao, Dabeeru C %A Redline, Susan %A van Heemst, Diana %K Blood Pressure %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Polymorphism, Single Nucleotide %K Sleep %X

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

%B Mol Psychiatry %V 26 %P 6293-6304 %8 2021 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/33859359?dopt=Abstract %R 10.1038/s41380-021-01087-0 %0 Journal Article %J Nat Genet %D 2021 %T Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. %A Surendran, Praveen %A Feofanova, Elena V %A Lahrouchi, Najim %A Ntalla, Ioanna %A Karthikeyan, Savita %A Cook, James %A Chen, Lingyan %A Mifsud, Borbala %A Yao, Chen %A Kraja, Aldi T %A Cartwright, James H %A Hellwege, Jacklyn N %A Giri, Ayush %A Tragante, Vinicius %A Thorleifsson, Gudmar %A Liu, Dajiang J %A Prins, Bram P %A Stewart, Isobel D %A Cabrera, Claudia P %A Eales, James M %A Akbarov, Artur %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Braithwaite, Vickie S %A Brody, Jennifer A %A Daw, E Warwick %A Warren, Helen R %A Drenos, Fotios %A Nielsen, Sune Fallgaard %A Faul, Jessica D %A Fauman, Eric B %A Fava, Cristiano %A Ferreira, Teresa %A Foley, Christopher N %A Franceschini, Nora %A Gao, He %A Giannakopoulou, Olga %A Giulianini, Franco %A Gudbjartsson, Daniel F %A Guo, Xiuqing %A Harris, Sarah E %A Havulinna, Aki S %A Helgadottir, Anna %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kanoni, Stavroula %A Kontto, Jukka %A Larson, Martin G %A Li-Gao, Ruifang %A Lindström, Jaana %A Lotta, Luca A %A Lu, Yingchang %A Luan, Jian'an %A Mahajan, Anubha %A Malerba, Giovanni %A Masca, Nicholas G D %A Mei, Hao %A Menni, Cristina %A Mook-Kanamori, Dennis O %A Mosen-Ansorena, David %A Müller-Nurasyid, Martina %A Paré, Guillaume %A Paul, Dirk S %A Perola, Markus %A Poveda, Alaitz %A Rauramaa, Rainer %A Richard, Melissa %A Richardson, Tom G %A Sepúlveda, Nuno %A Sim, Xueling %A Smith, Albert V %A Smith, Jennifer A %A Staley, James R %A Stanáková, Alena %A Sulem, Patrick %A Thériault, Sébastien %A Thorsteinsdottir, Unnur %A Trompet, Stella %A Varga, Tibor V %A Velez Edwards, Digna R %A Veronesi, Giovanni %A Weiss, Stefan %A Willems, Sara M %A Yao, Jie %A Young, Robin %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing-Hua %A Zhao, Wei %A Zhao, Wei %A Evangelou, Evangelos %A Aeschbacher, Stefanie %A Asllanaj, Eralda %A Blankenberg, Stefan %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Brandslund, Ivan %A Braund, Peter S %A Burgess, Stephen %A Cho, Kelly %A Christensen, Cramer %A Connell, John %A Mutsert, Renée de %A Dominiczak, Anna F %A Dörr, Marcus %A Eiriksdottir, Gudny %A Farmaki, Aliki-Eleni %A Gaziano, J Michael %A Grarup, Niels %A Grove, Megan L %A Hallmans, Goran %A Hansen, Torben %A Have, Christian T %A Heiss, Gerardo %A Jørgensen, Marit E %A Jousilahti, Pekka %A Kajantie, Eero %A Kamat, Mihir %A Käräjämäki, Annemari %A Karpe, Fredrik %A Koistinen, Heikki A %A Kovesdy, Csaba P %A Kuulasmaa, Kari %A Laatikainen, Tiina %A Lannfelt, Lars %A Lee, I-Te %A Lee, Wen-Jane %A Linneberg, Allan %A Martin, Lisa W %A Moitry, Marie %A Nadkarni, Girish %A Neville, Matt J %A Palmer, Colin N A %A Papanicolaou, George J %A Pedersen, Oluf %A Peters, James %A Poulter, Neil %A Rasheed, Asif %A Rasmussen, Katrine L %A Rayner, N William %A Mägi, Reedik %A Renstrom, Frida %A Rettig, Rainer %A Rossouw, Jacques %A Schreiner, Pamela J %A Sever, Peter S %A Sigurdsson, Emil L %A Skaaby, Tea %A Sun, Yan V %A Sundström, Johan %A Thorgeirsson, Gudmundur %A Esko, Tõnu %A Trabetti, Elisabetta %A Tsao, Philip S %A Tuomi, Tiinamaija %A Turner, Stephen T %A Tzoulaki, Ioanna %A Vaartjes, Ilonca %A Vergnaud, Anne-Claire %A Willer, Cristen J %A Wilson, Peter W F %A Witte, Daniel R %A Yonova-Doing, Ekaterina %A Zhang, He %A Aliya, Naheed %A Almgren, Peter %A Amouyel, Philippe %A Asselbergs, Folkert W %A Barnes, Michael R %A Blakemore, Alexandra I %A Boehnke, Michael %A Bots, Michiel L %A Bottinger, Erwin P %A Buring, Julie E %A Chambers, John C %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Conen, David %A Correa, Adolfo %A Davey Smith, George %A Boer, Rudolf A de %A Deary, Ian J %A Dedoussis, George %A Deloukas, Panos %A Di Angelantonio, Emanuele %A Elliott, Paul %A Felix, Stephan B %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Franks, Stephen %A Frossard, Philippe %A Gambaro, Giovanni %A Gaunt, Tom R %A Groop, Leif %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hennig, Branwen J %A Herzig, Karl-Heinz %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kardia, Sharon L R %A Kee, Frank %A Kooner, Jaspal S %A Kooperberg, Charles %A Launer, Lenore J %A Lind, Lars %A Loos, Ruth J F %A Majumder, Abdulla Al Shafi %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Murray, Alison D %A Nordestgaard, Børge Grønne %A Orho-Melander, Marju %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmas, Walter %A Polasek, Ozren %A Porteous, David J %A Prentice, Andrew M %A Province, Michael A %A Relton, Caroline L %A Rice, Kenneth %A Ridker, Paul M %A Rolandsson, Olov %A Rosendaal, Frits R %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sattar, Naveed %A Sheu, Wayne H-H %A Smith, Blair H %A Soranzo, Nicole %A Spector, Timothy D %A Starr, John M %A Sebert, Sylvain %A Taylor, Kent D %A Lakka, Timo A %A Timpson, Nicholas J %A Tobin, Martin D %A van der Harst, Pim %A van der Meer, Peter %A Ramachandran, Vasan S %A Verweij, Niek %A Virtamo, Jarmo %A Völker, Uwe %A Weir, David R %A Zeggini, Eleftheria %A Charchar, Fadi J %A Wareham, Nicholas J %A Langenberg, Claudia %A Tomaszewski, Maciej %A Butterworth, Adam S %A Caulfield, Mark J %A Danesh, John %A Edwards, Todd L %A Holm, Hilma %A Hung, Adriana M %A Lindgren, Cecilia M %A Liu, Chunyu %A Manning, Alisa K %A Morris, Andrew P %A Morrison, Alanna C %A O'Donnell, Christopher J %A Psaty, Bruce M %A Saleheen, Danish %A Stefansson, Kari %A Eric Boerwinkle %A Chasman, Daniel I %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %B Nat Genet %V 53 %P 762 %8 2021 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33727701?dopt=Abstract %R 10.1038/s41588-021-00832-z %0 Journal Article %J Nat Genet %D 2020 %T Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. %A Surendran, Praveen %A Feofanova, Elena V %A Lahrouchi, Najim %A Ntalla, Ioanna %A Karthikeyan, Savita %A Cook, James %A Chen, Lingyan %A Mifsud, Borbala %A Yao, Chen %A Kraja, Aldi T %A Cartwright, James H %A Hellwege, Jacklyn N %A Giri, Ayush %A Tragante, Vinicius %A Thorleifsson, Gudmar %A Liu, Dajiang J %A Prins, Bram P %A Stewart, Isobel D %A Cabrera, Claudia P %A Eales, James M %A Akbarov, Artur %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Braithwaite, Vickie S %A Brody, Jennifer A %A Daw, E Warwick %A Warren, Helen R %A Drenos, Fotios %A Nielsen, Sune Fallgaard %A Faul, Jessica D %A Fauman, Eric B %A Fava, Cristiano %A Ferreira, Teresa %A Foley, Christopher N %A Franceschini, Nora %A Gao, He %A Giannakopoulou, Olga %A Giulianini, Franco %A Gudbjartsson, Daniel F %A Guo, Xiuqing %A Harris, Sarah E %A Havulinna, Aki S %A Helgadottir, Anna %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kanoni, Stavroula %A Kontto, Jukka %A Larson, Martin G %A Li-Gao, Ruifang %A Lindström, Jaana %A Lotta, Luca A %A Lu, Yingchang %A Luan, Jian'an %A Mahajan, Anubha %A Malerba, Giovanni %A Masca, Nicholas G D %A Mei, Hao %A Menni, Cristina %A Mook-Kanamori, Dennis O %A Mosen-Ansorena, David %A Müller-Nurasyid, Martina %A Paré, Guillaume %A Paul, Dirk S %A Perola, Markus %A Poveda, Alaitz %A Rauramaa, Rainer %A Richard, Melissa %A Richardson, Tom G %A Sepúlveda, Nuno %A Sim, Xueling %A Smith, Albert V %A Smith, Jennifer A %A Staley, James R %A Stanáková, Alena %A Sulem, Patrick %A Thériault, Sébastien %A Thorsteinsdottir, Unnur %A Trompet, Stella %A Varga, Tibor V %A Velez Edwards, Digna R %A Veronesi, Giovanni %A Weiss, Stefan %A Willems, Sara M %A Yao, Jie %A Young, Robin %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing-Hua %A Zhao, Wei %A Zhao, Wei %A Evangelou, Evangelos %A Aeschbacher, Stefanie %A Asllanaj, Eralda %A Blankenberg, Stefan %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Brandslund, Ivan %A Braund, Peter S %A Burgess, Stephen %A Cho, Kelly %A Christensen, Cramer %A Connell, John %A Mutsert, Renée de %A Dominiczak, Anna F %A Dörr, Marcus %A Eiriksdottir, Gudny %A Farmaki, Aliki-Eleni %A Gaziano, J Michael %A Grarup, Niels %A Grove, Megan L %A Hallmans, Goran %A Hansen, Torben %A Have, Christian T %A Heiss, Gerardo %A Jørgensen, Marit E %A Jousilahti, Pekka %A Kajantie, Eero %A Kamat, Mihir %A Käräjämäki, Annemari %A Karpe, Fredrik %A Koistinen, Heikki A %A Kovesdy, Csaba P %A Kuulasmaa, Kari %A Laatikainen, Tiina %A Lannfelt, Lars %A Lee, I-Te %A Lee, Wen-Jane %A Linneberg, Allan %A Martin, Lisa W %A Moitry, Marie %A Nadkarni, Girish %A Neville, Matt J %A Palmer, Colin N A %A Papanicolaou, George J %A Pedersen, Oluf %A Peters, James %A Poulter, Neil %A Rasheed, Asif %A Rasmussen, Katrine L %A Rayner, N William %A Mägi, Reedik %A Renstrom, Frida %A Rettig, Rainer %A Rossouw, Jacques %A Schreiner, Pamela J %A Sever, Peter S %A Sigurdsson, Emil L %A Skaaby, Tea %A Sun, Yan V %A Sundström, Johan %A Thorgeirsson, Gudmundur %A Esko, Tõnu %A Trabetti, Elisabetta %A Tsao, Philip S %A Tuomi, Tiinamaija %A Turner, Stephen T %A Tzoulaki, Ioanna %A Vaartjes, Ilonca %A Vergnaud, Anne-Claire %A Willer, Cristen J %A Wilson, Peter W F %A Witte, Daniel R %A Yonova-Doing, Ekaterina %A Zhang, He %A Aliya, Naheed %A Almgren, Peter %A Amouyel, Philippe %A Asselbergs, Folkert W %A Barnes, Michael R %A Blakemore, Alexandra I %A Boehnke, Michael %A Bots, Michiel L %A Bottinger, Erwin P %A Buring, Julie E %A Chambers, John C %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Conen, David %A Correa, Adolfo %A Davey Smith, George %A Boer, Rudolf A de %A Deary, Ian J %A Dedoussis, George %A Deloukas, Panos %A Di Angelantonio, Emanuele %A Elliott, Paul %A Felix, Stephan B %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Franks, Stephen %A Frossard, Philippe %A Gambaro, Giovanni %A Gaunt, Tom R %A Groop, Leif %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hennig, Branwen J %A Herzig, Karl-Heinz %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kardia, Sharon L R %A Kee, Frank %A Kooner, Jaspal S %A Kooperberg, Charles %A Launer, Lenore J %A Lind, Lars %A Loos, Ruth J F %A Majumder, Abdulla Al Shafi %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Murray, Alison D %A Nordestgaard, Børge Grønne %A Orho-Melander, Marju %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmas, Walter %A Polasek, Ozren %A Porteous, David J %A Prentice, Andrew M %A Province, Michael A %A Relton, Caroline L %A Rice, Kenneth %A Ridker, Paul M %A Rolandsson, Olov %A Rosendaal, Frits R %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sattar, Naveed %A Sheu, Wayne H-H %A Smith, Blair H %A Soranzo, Nicole %A Spector, Timothy D %A Starr, John M %A Sebert, Sylvain %A Taylor, Kent D %A Lakka, Timo A %A Timpson, Nicholas J %A Tobin, Martin D %A van der Harst, Pim %A van der Meer, Peter %A Ramachandran, Vasan S %A Verweij, Niek %A Virtamo, Jarmo %A Völker, Uwe %A Weir, David R %A Zeggini, Eleftheria %A Charchar, Fadi J %A Wareham, Nicholas J %A Langenberg, Claudia %A Tomaszewski, Maciej %A Butterworth, Adam S %A Caulfield, Mark J %A Danesh, John %A Edwards, Todd L %A Holm, Hilma %A Hung, Adriana M %A Lindgren, Cecilia M %A Liu, Chunyu %A Manning, Alisa K %A Morris, Andrew P %A Morrison, Alanna C %A O'Donnell, Christopher J %A Psaty, Bruce M %A Saleheen, Danish %A Stefansson, Kari %A Eric Boerwinkle %A Chasman, Daniel I %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %K Blood Pressure %K GATA5 Transcription Factor %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Hypertension %K Mutation %K Phospholipase C beta %K Polymorphism, Single Nucleotide %X

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), 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.

%B Nat Genet %V 52 %P 1314-1332 %8 2020 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33230300?dopt=Abstract %R 10.1038/s41588-020-00713-x %0 Journal Article %J Hum Genet %D 2019 %T Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. %A He, Karen Y %A Li, Xiaoyin %A Kelly, Tanika N %A Liang, Jingjing %A Cade, Brian E %A Assimes, Themistocles L %A Becker, Lewis C %A Beitelshees, Amber L %A Bress, Adam P %A Chang, Yen-Pei Christy %A Chen, Yii-Der Ida %A de Vries, Paul S %A Fox, Ervin R %A Franceschini, Nora %A Furniss, Anna %A Gao, Yan %A Guo, Xiuqing %A Haessler, Jeffrey %A Hwang, Shih-Jen %A Irvin, Marguerite Ryan %A Kalyani, Rita R %A Liu, Ching-Ti %A Liu, Chunyu %A Martin, Lisa Warsinger %A Montasser, May E %A Muntner, Paul M %A Mwasongwe, Stanford %A Palmas, Walter %A Reiner, Alex P %A Shimbo, Daichi %A Smith, Jennifer A %A Snively, Beverly M %A Yanek, Lisa R %A Eric Boerwinkle %A Correa, Adolfo %A Cupples, L Adrienne %A He, Jiang %A Kardia, Sharon L R %A Kooperberg, Charles %A Mathias, Rasika A %A Mitchell, Braxton D %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rao, D C %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Chakravarti, Aravinda %A Morrison, Alanna C %A Levy, Daniel %A Arnett, Donna K %A Redline, Susan %A Zhu, Xiaofeng %K Alternative Splicing %K Blood Pressure %K Chromosomes, Human, Pair 16 %K Exome %K Female %K Follow-Up Studies %K Genetic Linkage %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Recombinases %K RNA Splicing Factors %X

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

%B Hum Genet %V 138 %P 199-210 %8 2019 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30671673?dopt=Abstract %R 10.1007/s00439-019-01975-0 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Eric Boerwinkle %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A de Borst, Martin H %A de Geus, Eco J %A Deary, Ian J %A Deelen, Joris %A Del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Åsa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %K Adult %K Aged %K Aged, 80 and over %K Blood Pressure %K Cardiovascular Diseases %K Cells, Cultured %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Testing %K Genetics, Population %K Genome-Wide Association Study %K Human Umbilical Vein Endothelial Cells %K Humans %K Hypertension %K Life Style %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract %R 10.1038/s41588-018-0205-x %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Eric Boerwinkle %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Protein-Lysine 6-Oxidase %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 Dec 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30510157?dopt=Abstract %R 10.1038/s41467-018-07340-5 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Eric Boerwinkle %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Goran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Blood Pressure %K Cohort Studies %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Racial Groups %K Young Adult %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Genet %D 2018 %T Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Eric Boerwinkle %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A de Borst, Martin H %A de Geus, Eco J %A Deary, Ian J %A Deelen, Joris %A Del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Åsa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

%B Nat Genet %V 50 %P 1755 %8 2018 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/30429575?dopt=Abstract %R 10.1038/s41588-018-0297-3 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Eric Boerwinkle %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10; replication: N = 7,182, p < 1.6 × 10). The replicated methylation sites are heritable (h > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29198723?dopt=Abstract %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Genet Epidemiol %D 2016 %T An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. %A Sung, Yun Ju %A Winkler, Thomas W %A Manning, Alisa K %A Aschard, Hugues %A Gudnason, Vilmundur %A Harris, Tamara B %A Smith, Albert V %A Eric Boerwinkle %A Brown, Michael R %A Morrison, Alanna C %A Fornage, Myriam %A Lin, Li-An %A Richard, Melissa %A Bartz, Traci M %A Psaty, Bruce M %A Hayward, Caroline %A Polasek, Ozren %A Marten, Jonathan %A Rudan, Igor %A Feitosa, Mary F %A Kraja, Aldi T %A Province, Michael A %A Deng, Xuan %A Fisher, Virginia A %A Zhou, Yanhua %A Bielak, Lawrence F %A Smith, Jennifer %A Huffman, Jennifer E %A Padmanabhan, Sandosh %A Smith, Blair H %A Ding, Jingzhong %A Liu, Yongmei %A Lohman, Kurt %A Bouchard, Claude %A Rankinen, Tuomo %A Rice, Treva K %A Arnett, Donna %A Schwander, Karen %A Guo, Xiuqing %A Palmas, Walter %A Rotter, Jerome I %A Alfred, Tamuno %A Bottinger, Erwin P %A Loos, Ruth J F %A Amin, Najaf %A Franco, Oscar H %A van Duijn, Cornelia M %A Vojinovic, Dina %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Kardia, Sharon %A Zhu, Xiaofeng %A Rice, Kenneth %A Borecki, Ingrid B %A Rao, Dabeeru C %A Gauderman, W James %A Cupples, L Adrienne %K Blood Pressure %K Cohort Studies %K Databases, Factual %K Family %K Gene Frequency %K Gene-Environment Interaction %K Genome-Wide Association Study %K Genotype %K Humans %K Phenotype %K Smoking %X

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

%B Genet Epidemiol %V 40 %P 404-15 %8 2016 Jul %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract %R 10.1002/gepi.21978 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. %A Yu, Bing %A Pulit, Sara L %A Hwang, Shih-Jen %A Brody, Jennifer A %A Amin, Najaf %A Auer, Paul L %A Bis, Joshua C %A Eric Boerwinkle %A Burke, Gregory L %A Chakravarti, Aravinda %A Correa, Adolfo %A Dreisbach, Albert W %A Franco, Oscar H %A Ehret, Georg B %A Franceschini, Nora %A Hofman, Albert %A Lin, Dan-Yu %A Ginger A Metcalf %A Musani, Solomon K %A Donna M Muzny %A Palmas, Walter %A Raffel, Leslie %A Reiner, Alex %A Rice, Ken %A Rotter, Jerome I %A Veeraraghavan, Narayanan %A Fox, Ervin %A Guo, Xiuqing %A North, Kari E %A Richard A Gibbs %A van Duijn, Cornelia M %A Psaty, Bruce M %A Levy, Daniel %A Newton-Cheh, Christopher %A Morrison, Alanna C %K Alleles %K Black People %K Blood Pressure %K Chloride Channels %K Exome %K Female %K Gene Frequency %K Humans %K Hypertension %K Male %K Risk Factors %K White People %X

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

%B Circ Cardiovasc Genet %V 9 %P 64-70 %8 2016 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001215