Searched for: person:chakra01 or evrong01
Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits
Evangelou, Evangelos; Warren, Helen R; Mosen-Ansorena, David; Mifsud, Borbala; Pazoki, Raha; Gao, He; Ntritsos, Georgios; Dimou, Niki; Cabrera, Claudia P; Karaman, Ibrahim; Ng, Fu Liang; Evangelou, Marina; Witkowska, Katarzyna; Tzanis, Evan; Hellwege, Jacklyn N; Giri, Ayush; Velez Edwards, Digna R; Sun, Yan V; Cho, Kelly; Gaziano, J Michael; Wilson, Peter W F; Tsao, Philip S; Kovesdy, Csaba P; Esko, Tonu; Mägi, Reedik; Milani, Lili; Almgren, Peter; Boutin, Thibaud; Debette, Stéphanie; Ding, Jun; Giulianini, Franco; Holliday, Elizabeth G; Jackson, Anne U; Li-Gao, Ruifang; Lin, Wei-Yu; Luan, Jian'an; Mangino, Massimo; Oldmeadow, Christopher; Prins, Bram Peter; Qian, Yong; Sargurupremraj, Muralidharan; Shah, Nabi; Surendran, Praveen; Thériault, Sébastien; Verweij, Niek; Willems, Sara M; Zhao, Jing-Hua; Amouyel, Philippe; Connell, John; de Mutsert, Renée; Doney, Alex S F; Farrall, Martin; Menni, Cristina; Morris, Andrew D; Noordam, Raymond; Paré, Guillaume; Poulter, Neil R; Shields, Denis C; Stanton, Alice; Thom, Simon; Abecasis, Gonçalo; Amin, Najaf; Arking, Dan E; Ayers, Kristin L; Barbieri, Caterina M; Batini, Chiara; Bis, Joshua C; Blake, Tineka; Bochud, Murielle; Boehnke, Michael; Boerwinkle, Eric; Boomsma, Dorret I; Bottinger, Erwin P; Braund, Peter S; Brumat, Marco; Campbell, Archie; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C; Chauhan, Ganesh; Ciullo, Marina; Cocca, Massimiliano; Collins, Francis; Cordell, Heather J; Davies, Gail; Borst, Martin H de; Geus, Eco J de; Deary, Ian J; Deelen, Joris; Del Greco M, Fabiola; Demirkale, Cumhur Yusuf; Dörr, Marcus; Ehret, Georg B; Elosua, Roberto; Enroth, Stefan; Erzurumluoglu, A Mesut; Ferreira, Teresa; FrÃ¥nberg, Mattias; Franco, Oscar H; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Gieger, Christian; Girotto, Giorgia; Goel, Anuj; Gow, Alan J; Gudnason, Vilmundur; Guo, Xiuqing; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Harris, Sarah E; Hartman, Catharina A; Havulinna, Aki S; Hicks, Andrew A; Hofer, Edith; Hofman, Albert; Hottenga, Jouke-Jan; Huffman, Jennifer E; Hwang, Shih-Jen; Ingelsson, Erik; James, Alan; Jansen, Rick; Jarvelin, Marjo-Riitta; Joehanes, Roby; Johansson, Ã…sa; Johnson, Andrew D; Joshi, Peter K; Jousilahti, Pekka; Jukema, J Wouter; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Keavney, Bernard D; Khaw, Kay-Tee; Knekt, Paul; Knight, Joanne; Kolcic, Ivana; Kooner, Jaspal S; Koskinen, Seppo; Kristiansson, Kati; Kutalik, Zoltan; Laan, Maris; Larson, Marty; Launer, Lenore J; Lehne, Benjamin; Lehtimäki, Terho; Liewald, David C M; Lin, Li; Lind, Lars; Lindgren, Cecilia M; Liu, YongMei; Loos, Ruth J F; Lopez, Lorna M; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Mahajan, Anubha; Mamasoula, Chrysovalanto; Marrugat, Jaume; Marten, Jonathan; Milaneschi, Yuri; Morgan, Anna; Morris, Andrew P; Morrison, Alanna C; Munson, Peter J; Nalls, Mike A; Nandakumar, Priyanka; Nelson, Christopher P; Niiranen, Teemu; Nolte, Ilja M; Nutile, Teresa; Oldehinkel, Albertine J; Oostra, Ben A; O'Reilly, Paul F; Org, Elin; Padmanabhan, Sandosh; Palmas, Walter; Palotie, Aarno; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peters, Annette; Polasek, Ozren; Pramstaller, Peter P; Nguyen, Quang Tri; Raitakari, Olli T; Ren, Meixia; Rettig, Rainer; Rice, Kenneth; Ridker, Paul M; Ried, Janina S; Riese, Harriëtte; Ripatti, Samuli; Robino, Antonietta; Rose, Lynda M; Rotter, Jerome I; Rudan, Igor; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia F; Salomaa, Veikko; Samani, Nilesh J; Sarin, Antti-Pekka; Schmidt, Reinhold; Schmidt, Helena; Shrine, Nick; Siscovick, David; Smith, Albert V; Snieder, Harold; Sõber, Siim; Sorice, Rossella; Starr, John M; Stott, David J; Strachan, David P; Strawbridge, Rona J; Sundström, Johan; Swertz, Morris A; Taylor, Kent D; Teumer, Alexander; Tobin, Martin D; Tomaszewski, Maciej; Toniolo, Daniela; Traglia, Michela; Trompet, Stella; Tuomilehto, Jaakko; Tzourio, Christophe; Uitterlinden, André G; Vaez, Ahmad; van der Most, Peter J; van Duijn, Cornelia M; Vergnaud, Anne-Claire; Verwoert, Germaine C; Vitart, Veronique; Völker, Uwe; Vollenweider, Peter; Vuckovic, Dragana; Watkins, Hugh; Wild, Sarah H; Willemsen, Gonneke; Wilson, James F; Wright, Alan F; Yao, Jie; Zemunik, Tatijana; Zhang, Weihua; Attia, John R; Butterworth, Adam S; Chasman, Daniel I; Conen, David; Cucca, Francesco; Danesh, John; Hayward, Caroline; Howson, Joanna M M; Laakso, Markku; Lakatta, Edward G; Langenberg, Claudia; Melander, Olle; Mook-Kanamori, Dennis O; Palmer, Colin N A; Risch, Lorenz; Scott, Robert A; Scott, Rodney J; Sever, Peter; Spector, Tim D; van der Harst, Pim; Wareham, Nicholas J; Zeggini, Eleftheria; Levy, Daniel; Munroe, Patricia B; Newton-Cheh, Christopher; Brown, Morris J; Metspalu, Andres; Hung, Adriana M; O'Donnell, Christopher J; Edwards, Todd L; Psaty, Bruce M; Tzoulaki, Ioanna; Barnes, Michael R; Wain, Louise V; Elliott, Paul; Caulfield, Mark J
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.
PMID: 30224653
ISSN: 1546-1718
CID: 3317072
Contributions of rare coding variants in hypotension syndrome genes to population blood pressure variation
Nandakumar, Priyanka; Morrison, Alanna C; Grove, Megan L; Boerwinkle, Eric; Chakravarti, Aravinda
Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population. The present study focuses on replicating the analyses completed by Ji et al to identify effects of rare variants in the population-based Atherosclerosis Risk in Communities (ARIC) study.We attempted to replicate the findings by Ji et al by applying their criteria to identify putative loss-of-function variants with allele frequency <0.001 and complete conservation across a set of orthologs, to exome sequencing data from 7444 European ancestry participants of the ARIC study.Although we failed to replicate the previous findings when applying their methods to the ARIC study data, we observed a similar effect when we restricted analyses to the subset of variants they observed.These results simultaneously support the utility of exome sequencing data for studying extremely rare coding variants in hypertension and underscore the need for improved filtering methods for identifying functional variants in human sequences.
PMCID:6113003
PMID: 30113482
ISSN: 1536-5964
CID: 3241042
RET somatic mutations are underrecognized in Hirschsprung disease
Jiang, Qian; Liu, Fang; Miao, Chunyue; Li, Qi; Zhang, Zhen; Xiao, Ping; Su, Lin; Yu, Kaihui; Chen, Xiaoli; Zhang, Feng; Chakravarti, Aravinda; Li, Long
PurposeWe aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.MethodsTargeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.ResultsWe identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%).ConclusionSomatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.Genetics in Medicine advance online publication, 26 October 2017; doi:10.1038/gim.2017.178.
PMID: 29261189
ISSN: 1530-0366
CID: 3150252
Newton E. Morton (1929-2018)
Sherman, Stephanie L; Rao, D C; Keats, Bronya J; Yee, Shirley; Spence, M Anne; Hassold, Terry J; Chakravarti, Aravinda; Elston, Robert C; Crolla, John A; Ennis, Sarah; Risch, Neil
PMID: 33220219
ISSN: 1537-6605
CID: 4706502
Cardiomyocytes have mosaic patterns of protein expression
Wang, Tony Y; Lee, Dongwon; Fox-Talbot, Karen; Arking, Dan E; Chakravarti, Aravinda; Halushka, Marc K
Skeletal myocytes have well-established fast and slow twitch fibers with unique gene and protein specific expression patterns. By immunohistochemical staining, these show a mosaic pattern across myocytes. We hypothesized cardiac myocytes may behave similarly where some proteins are differentially expressed between mature cardiomyocytes. We utilized the tool HPASubC on over 52,000 cardiac images of the Human Protein Atlas to identify differential protein expression patterns by immunohistochemistry across the cardiomyocytes. We matched identified proteins to open chromatin and gene expression data. We identified 143 putative proteins with mosaic patterns of expression across the cardiomyocytes. We validated four of these proteins (MYL3, MYL4, PAM, and MYOM1) and demonstrated unique atrial or ventricular patterns of expression for each. Acetylation of histone H3K27 at the promoters of these four genes were consistent with the atrial/ventricular expression patterns. Despite the generally accepted homogeneity of cardiomyocytes, a small subset of proteins varies between cardiomyocytes in a mosaic pattern. This fundamental process has been previously uncharacterized. These changes may inform on different functional and disease-related activities of proteins in individual cardiomyocytes.
PMCID:5940500
PMID: 29677652
ISSN: 1879-1336
CID: 3141632
Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations [Correction]
Liang, Jingjing; Le, Thu H; Velez Edwards, Digna R; Tayo, Bamidele O; Gaulton, Kyle J; Smith, Jennifer A; Lu, Yingchang; Jensen, Richard A; Chen, Guanjie; Yanek, Lisa R; Schwander, Karen; Tajuddin, Salman M; Sofer, Tamar; Kim, Wonji; Kayima, James; McKenzie, Colin A; Fox, Ervin; Nalls, Michael A; Young, J Hunter; Sun, Yan V; Lane, Jacqueline M; Cechova, Sylvia; Zhou, Jie; Tang, Hua; Fornage, Myriam; Musani, Solomon K; Wang, Heming; Lee, Juyoung; Adeyemo, Adebowale; Dreisbach, Albert W; Forrester, Terrence; Chu, Pei-Lun; Cappola, Anne; Evans, Michele K; Morrison, Alanna C; Martin, Lisa W; Wiggins, Kerri L; Hui, Qin; Zhao, Wei; Jackson, Rebecca D; Ware, Erin B; Faul, Jessica D; Reiner, Alex P; Bray, Michael; Denny, Joshua C; Mosley, Thomas H; Palmas, Walter; Guo, Xiuqing; Papanicolaou, George J; Penman, Alan D; Polak, Joseph F; Rice, Kenneth; Taylor, Ken D; Boerwinkle, Eric; Bottinger, Erwin P; Liu, Kiang; Risch, Neil; Hunt, Steven C; Kooperberg, Charles; Zonderman, Alan B; Laurie, Cathy C; Becker, Diane M; Cai, Jianwen; Loos, Ruth J F; Psaty, Bruce M; Weir, David R; Kardia, Sharon L R; Arnett, Donna K; Won, Sungho; Edwards, Todd L; Redline, Susan; Cooper, Richard S; Rao, D C; Rotter, Jerome I; Rotimi, Charles; Levy, Daniel; Chakravarti, Aravinda; Zhu, Xiaofeng; Franceschini, Nora
[This corrects the article DOI: 10.1371/journal.pgen.1006728.].
PMCID:5947884
PMID: 29750786
ISSN: 1553-7404
CID: 3141642
Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus
Fadista, João; Lund, Marie; Skotte, Line; Geller, Frank; Nandakumar, Priyanka; Chatterjee, Sumantra; Matsson, Hans; Granström, Anna Löf; Wester, Tomas; Salo, Perttu; Virtanen, Valtter; Carstensen, Lisbeth; Bybjerg-Grauholm, Jonas; Hougaard, David Michael; Pakarinen, Mikko; Perola, Markus; Nordenskjöld, Agneta; Chakravarti, Aravinda; Melbye, Mads; Feenstra, Bjarke
Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.
PMCID:5891499
PMID: 29379196
ISSN: 1476-5438
CID: 3141602
A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure
Sung, Yun J; Winkler, Thomas W; de Las Fuentes, Lisa; Bentley, Amy R; Brown, Michael R; Kraja, Aldi T; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Kilpeläinen, Tuomas O; Richard, Melissa A; Noordam, Raymond; Aslibekyan, Stella; Aschard, Hugues; Bartz, Traci M; Dorajoo, Rajkumar; Liu, Yongmei; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M; Tayo, Bamidele O; Warren, Helen R; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E; Hartwig, Fernando Pires; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Kühnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; 'an Luan, Jian; McKenzie, Colin A; Meian, He; Nelson, Christopher P; Rauramaa, Rainer; Schupf, Nicole; Scott, Robert A; Sheu, Wayne H H; StanÄáková, Alena; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Wang, Heming; Wang, Yajuan; Ware, Erin B; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Alfred, Tamuno; Amin, Najaf; Arking, Dan; Aung, Tin; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Braund, Peter S; Brody, Jennifer A; Broeckel, Ulrich; Cabrera, Claudia P; Cade, Brian; Caizheng, Yu; Campbell, Archie; Canouil, Mickaël; Chakravarti, Aravinda; Chauhan, Ganesh; Christensen, Kaare; Cocca, Massimiliano; Collins, Francis S; Connell, John M; de Mutsert, Renée; de Silva, H Janaka; Debette, Stephanie; Dörr, Marcus; Duan, Qing; Eaton, Charles B; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D; Fisher, Virginia A; Forouhi, Nita G; Franco, Oscar H; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Graff, Misa; Gu, C Charles; Gu, Dongfeng; Gupta, Preeti; Hagenaars, Saskia P; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hofman, Albert; Howard, Barbara V; Hunt, Steven; Irvin, Marguerite R; Jia, Yucheng; Joehanes, Roby; Justice, Anne E; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A; Komulainen, Pirjo; Kooperberg, Charles; Krieger, Jose E; Kubo, Michiaki; Kuusisto, Johanna; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lim, Sing Hui; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Kiang; Liu, Yeheng; Loh, Marie; Lohman, Kurt K; Long, Jirong; Louie, Tin; Mägi, Reedik; Mahajan, Anubha; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Morris, Andrew P; Mosley, Thomas H; Munson, Peter; Murray, Alison D; Nalls, Mike A; Nasri, Ubaydah; Norris, Jill M; North, Kari; Ogunniyi, Adesola; Padmanabhan, Sandosh; Palmas, Walter R; Palmer, Nicholette D; Pankow, James S; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Raitakari, Olli T; Renström, Frida; Rice, Treva K; Ridker, Paul M; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Sabanayagam, Charumathi; Salako, Babatunde L; Sandow, Kevin; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Seshadri, Sudha; Sever, Peter; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; Waldenberger, Melanie; Wang, Lihua; Wang, Ya X; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Chen, Yii-Der Ida; de Faire, Ulf; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Forrester, Terrence; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost B; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Lehtimäki, Terho; Liang, Kae-Woei; Magnusson, Patrik K E; Newman, Anne B; Oldehinkel, Albertine J; Pereira, Alexandre C; Redline, Susan; Rettig, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Kamatani, Yoichiro; Laurie, Cathy C; Bouchard, Claude; Cooper, Richard S; Evans, Michele K; Gudnason, Vilmundur; Kardia, Sharon L R; Kritchevsky, Stephen B; Levy, Daniel; O'Connell, Jeff R; Psaty, Bruce M; van Dam, Rob M; Sims, Mario; Arnett, Donna K; Mook-Kanamori, Dennis O; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; Fornage, Myriam; Rotimi, Charles N; Province, Michael A; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Reiner, Alex P; Rotter, Jerome I; Zhu, Xiaofeng; Bierut, Laura J; Gauderman, W James; Caulfield, Mark J; Elliott, Paul; Rice, Kenneth; Munroe, Patricia B; Morrison, Alanna C; Cupples, L Adrienne; Rao, Dabeeru C; Chasman, Daniel I
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
PMCID:5985266
PMID: 29455858
ISSN: 1537-6605
CID: 3141612
The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis
Fernández-Rhodes, Lindsay; Malinowski, Jennifer R; Wang, Yujie; Tao, Ran; Pankratz, Nathan; Jeff, Janina M; Yoneyama, Sachiko; Carty, Cara L; Setiawan, V Wendy; Le Marchand, Loic; Haiman, Christopher; Corbett, Steven; Demerath, Ellen; Heiss, Gerardo; Gross, Myron; Buzkova, Petra; Crawford, Dana C; Hunt, Steven C; Rao, D C; Schwander, Karen; Chakravarti, Aravinda; Gottesman, Omri; Abul-Husn, Noura S; Bottinger, Erwin P; Loos, Ruth J F; Raffel, Leslie J; Yao, Jie; Guo, Xiuqing; Bielinski, Suzette J; Rotter, Jerome I; Vaidya, Dhananjay; Chen, Yii-Der Ida; Castañeda, Sheila F; Daviglus, Martha; Kaplan, Robert; Talavera, Gregory A; Ryckman, Kelli K; Peters, Ulrike; Ambite, Jose Luis; Buyske, Steven; Hindorff, Lucia; Kooperberg, Charles; Matise, Tara; Franceschini, Nora; North, Kari E
Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
PMCID:6059436
PMID: 30044860
ISSN: 1932-6203
CID: 3978452
Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
Feitosa, Mary F; Kraja, Aldi T; Chasman, Daniel I; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Bentley, Amy R; Brown, Michael R; Schwander, Karen; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P; Horimoto, Andrea R V R; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Wojczynski, Mary K; Alver, Maris; Boissel, Mathilde; Cai, Qiuyin; Campbell, Archie; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; He, Meian; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Luan, Jian'an; Matoba, Nana; Nolte, Ilja M; Padmanabhan, Sandosh; Riaz, Muhammad; Rueedi, Rico; Robino, Antonietta; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; StanÄáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Vitart, Veronique; Wang, Yajuan; Ware, Erin B; Warren, Helen R; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Boerwinkle, Eric; Borecki, Ingrid; Broeckel, Ulrich; Brown, Morris; Brumat, Marco; Burke, Gregory L; Canouil, Mickaël; Chakravarti, Aravinda; Charumathi, Sabanayagam; Ida Chen, Yii-Der; Connell, John M; Correa, Adolfo; de Las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Deng, Xuan; Ding, Jingzhong; Duan, Qing; Eaton, Charles B; Ehret, Georg; Eppinga, Ruben N; Evangelou, Evangelos; Faul, Jessica D; Felix, Stephan B; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gigante, Bruna; Gu, C Charles; Gu, Dongfeng; Hagenaars, Saskia P; Hallmans, Göran; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Howard, Barbara V; Ikram, M Arfan; John, Ulrich; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Krieger, José E; Kritchevsky, Stephen B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lin, Shiow; Liu, Jianjun; Liu, Jingmin; Loh, Marie; Louie, Tin; Mägi, Reedik; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Momozawa, Yukihide; Nalls, Mike A; Nelson, Christopher P; Sotoodehnia, Nona; Norris, Jill M; O'Connell, Jeff R; Palmer, Nicholette D; Perls, Thomas; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Roll, Kathryn; Rose, Lynda M; Rosendaal, Frits R; Rotter, Jerome I; Schmidt, Carsten O; Schreiner, Pamela J; Schupf, Nicole; Scott, William R; Sever, Peter S; Shi, Yuan; Sidney, Stephen; Sims, Mario; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Stringham, Heather M; Tan, Nicholas Y Q; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Turner, Stephen T; Uitterlinden, André G; Vollenweider, Peter; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Williams, Christine; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Jonas, Jost Bruno; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Kutalik, Zoltán; Laakso, Markku; Laurie, Cathy C; Leander, Karin; Lehtimäki, Terho; Study, Lifelines Cohort; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Polasek, Ozren; Porteous, David J; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Bouchard, Claude; Christensen, Kaare; Evans, Michele K; Gudnason, Vilmundur; Horta, Bernardo L; Kardia, Sharon L R; Liu, Yongmei; Pereira, Alexandre C; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Gauderman, W James; Zhu, Xiaofeng; Mook-Kanamori, Dennis O; Fornage, Myriam; Rotimi, Charles N; Cupples, L Adrienne; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Kooperberg, Charles; Palmas, Walter; Rice, Kenneth; Morrison, Alanna C; Elliott, Paul; Caulfield, Mark J; Munroe, Patricia B; Rao, Dabeeru C; Province, Michael A; Levy, Daniel
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.
PMCID:6005576
PMID: 29912962
ISSN: 1932-6203
CID: 3978442
