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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
Sung, Yun Ju; de Las Fuentes, Lisa; Winkler, Thomas W; Chasman, Daniel I; Bentley, Amy R; Kraja, Aldi T; Ntalla, Ioanna; Warren, Helen R; Guo, Xiuqing; Schwander, Karen; Manning, Alisa K; Brown, Michael R; Aschard, Hugues; Feitosa, Mary F; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Kilpeläinen, Tuomas O; Richard, Melissa A; Aslibekyan, Stella; Bartz, Traci M; Dorajoo, Rajkumar; Li, Changwei; Liu, Yongmei; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M; Tayo, Bamidele O; 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 P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kammerer, Candace M; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; Luan, Jian'an; Lyytikäinen, Leo-Pekka; McKenzie, Colin A; Nelson, Christopher P; Noordam, Raymond; Scott, Robert A; Sheu, Wayne H H; StanÄáková, Alena; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Waken, Robert J; 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 E; Aung, Tin; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Braund, Peter S; Brody, Jennifer A; Broeckel, Ulrich; Cade, Brian; Campbell, Archie; Canouil, Mickaël; Chakravarti, Aravinda; Cocca, Massimiliano; Collins, Francis S; Connell, John M; de Mutsert, Renée; de Silva, H Janaka; Dörr, Marcus; Duan, Qing; Eaton, Charles B; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D; Forouhi, Nita G; Franco, Oscar H; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Gu, C Charles; Gupta, Preeti; Hagenaars, Saskia P; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hofman, Albert; Howard, Barbara V; Hunt, Steven C; Irvin, Marguerite R; Jia, Yucheng; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A; Kooperberg, Charles B; Krieger, Jose E; Kubo, Michiaki; Kutalik, Zoltan; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Joseph H; Lehne, Benjamin; Levy, Daniel; Lewis, Cora E; Li, Yize; Lim, Sing Hui; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Yeheng; Loh, Marie; Lohman, Kurt K; Louie, Tin; Mägi, Reedik; Matsuda, Koichi; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Mosley, Thomas H; Nalls, Mike A; Nasri, Ubaydah; O'Connell, Jeff R; Ogunniyi, Adesola; Palmas, Walter R; Palmer, Nicholette D; Pankow, James S; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Porteous, David; 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; Sever, Peter; Sims, Mario; Sitlani, Colleen M; Smith, Blair H; 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 Xing; Wei, Wen Bin; Wilson, Gregory; Wojczynski, Mary K; Xiang, Yong-Bing; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Chen, Yii-Der Ida; Weir, David R; de Faire, Ulf; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Forrester, Terrence; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost Bruno; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Lehtimäki, Terho; Liang, Kae-Woei; Magnusson, Patrik K E; Oldehinkel, Albertine J; Pereira, Alexandre C; Perls, Thomas; Rauramaa, Rainer; Redline, Susan; Rettig, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Wickremasinghe, Ananda R; Wu, Tangchun; Kamatani, Yoichiro; Laurie, Cathy C; Bouchard, Claude; Cooper, Richard S; Evans, Michele K; Gudnason, Vilmundur; Hixson, James; Kardia, Sharon L R; Kritchevsky, Stephen B; Psaty, Bruce M; van Dam, Rob M; Arnett, Donna K; Mook-Kanamori, Dennis O; Fornage, Myriam; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Reiner, Alex P; Rotimi, Charles N; Bierut, Laura J; Zhu, Xiaofeng; Cupples, L Adrienne; Province, Michael A; Rotter, Jerome I; Franks, Paul W; Rice, Kenneth; Elliott, Paul; Caulfield, Mark J; Gauderman, W James; Munroe, Patricia B; Rao, Dabeeru C; Morrison, Alanna C
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
PMID: 31127295
ISSN: 1460-2083
CID: 3967142
Multiple SCN5A variant enhancers modulate its cardiac gene expression and the QT interval
Kapoor, Ashish; Lee, Dongwon; Zhu, Luke; Soliman, Elsayed Z; Grove, Megan L; Boerwinkle, Eric; Arking, Dan E; Chakravarti, Aravinda
The rationale for genome-wide association study (GWAS) results is sequence variation in cis-regulatory elements (CREs) modulating a target gene's expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the SCN5A-SCN10A locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict SCN5A cardiac gene expression and QTi association. Although all 13 variants could explain SCN5A gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.
PMID: 31068470
ISSN: 1091-6490
CID: 3909312
Molecular Genetic Anatomy and Risk Profile of Hirschsprung's Disease
Tilghman, Joseph M; Ling, Albee Y; Turner, Tychele N; Sosa, Maria X; Krumm, Niklas; Chatterjee, Sumantra; Kapoor, Ashish; Coe, Bradley P; Nguyen, Khanh-Dung H; Gupta, Namrata; Gabriel, Stacey; Eichler, Evan E; Berrios, Courtney; Chakravarti, Aravinda
BACKGROUND:Hirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. METHODS:We genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos. RESULTS:). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120). CONCLUSIONS:. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).
PMID: 30970187
ISSN: 1533-4406
CID: 3826322
Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data
He, Karen Y; Li, Xiaoyin; Kelly, Tanika N; Liang, Jingjing; Cade, Brian E; Assimes, Themistocles L; Becker, Lewis C; Beitelshees, Amber L; Bress, Adam P; Chang, Yen-Pei Christy; Chen, Yii-Der Ida; de Vries, Paul S; Fox, Ervin R; Franceschini, Nora; Furniss, Anna; Gao, Yan; Guo, Xiuqing; Haessler, Jeffrey; Hwang, Shih-Jen; Irvin, Marguerite Ryan; Kalyani, Rita R; Liu, Ching-Ti; Liu, Chunyu; Martin, Lisa Warsinger; Montasser, May E; Muntner, Paul M; Mwasongwe, Stanford; Palmas, Walter; Reiner, Alex P; Shimbo, Daichi; Smith, Jennifer A; Snively, Beverly M; Yanek, Lisa R; Boerwinkle, Eric; Correa, Adolfo; Cupples, L Adrienne; He, Jiang; Kardia, Sharon L R; Kooperberg, Charles; Mathias, Rasika A; Mitchell, Braxton D; Psaty, Bruce M; Vasan, Ramachandran S; Rao, D C; Rich, Stephen S; Rotter, Jerome I; Wilson, James G; Chakravarti, Aravinda; Morrison, Alanna C; Levy, Daniel; Arnett, Donna K; Redline, Susan; Zhu, Xiaofeng
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 × 10-4) 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.
PMID: 30671673
ISSN: 1432-1203
CID: 3610552
Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31
Wang, Heming; Nandakumar, Priyanka; Tekola-Ayele, Fasil; Tayo, Bamidele O; Ware, Erin B; Gu, C Charles; Lu, Yingchang; Yao, Jie; Zhao, Wei; Smith, Jennifer A; Hellwege, Jacklyn N; Guo, Xiuqing; Edwards, Todd L; Loos, Ruth J F; Arnett, Donna K; Fornage, Myriam; Rotimi, Charles; Kardia, Sharon L R; Cooper, Richard S; Rao, D C; Ehret, Georg; Chakravarti, Aravinda; Zhu, Xiaofeng
High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.
PMCID:6336803
PMID: 30262922
ISSN: 1476-5438
CID: 3975192
Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits
Kraja, Aldi T; Liu, Chunyu; Fetterman, Jessica L; Graff, Mariaelisa; Have, Christian Theil; Gu, Charles; Yanek, Lisa R; Feitosa, Mary F; Arking, Dan E; Chasman, Daniel I; Young, Kristin; Ligthart, Symen; Hill, W David; Weiss, Stefan; Luan, Jian'an; Giulianini, Franco; Li-Gao, Ruifang; Hartwig, Fernando P; Lin, Shiow J; Wang, Lihua; Richardson, Tom G; Yao, Jie; Fernandez, Eliana P; Ghanbari, Mohsen; Wojczynski, Mary K; Lee, Wen-Jane; Argos, Maria; Armasu, Sebastian M; Barve, Ruteja A; Ryan, Kathleen A; An, Ping; Baranski, Thomas J; Bielinski, Suzette J; Bowden, Donald W; Broeckel, Ulrich; Christensen, Kaare; Chu, Audrey Y; Corley, Janie; Cox, Simon R; Uitterlinden, Andre G; Rivadeneira, Fernando; Cropp, Cheryl D; Daw, E Warwick; van Heemst, Diana; de Las Fuentes, Lisa; Gao, He; Tzoulaki, Ioanna; Ahluwalia, Tarunveer S; de Mutsert, Renée; Emery, Leslie S; Erzurumluoglu, A Mesut; Perry, James A; Fu, Mao; Forouhi, Nita G; Gu, Zhenglong; Hai, Yang; Harris, Sarah E; Hemani, Gibran; Hunt, Steven C; Irvin, Marguerite R; Jonsson, Anna E; Justice, Anne E; Kerrison, Nicola D; Larson, Nicholas B; Lin, Keng-Hung; Love-Gregory, Latisha D; Mathias, Rasika A; Lee, Joseph H; Nauck, Matthias; Noordam, Raymond; Ong, Ken K; Pankow, James; Patki, Amit; Pattie, Alison; Petersmann, Astrid; Qi, Qibin; Ribel-Madsen, Rasmus; Rohde, Rebecca; Sandow, Kevin; Schnurr, Theresia M; Sofer, Tamar; Starr, John M; Taylor, Adele M; Teumer, Alexander; Timpson, Nicholas J; de Haan, Hugoline G; Wang, Yujie; Weeke, Peter E; Williams, Christine; Wu, Hongsheng; Yang, Wei; Zeng, Donglin; Witte, Daniel R; Weir, Bruce S; Wareham, Nicholas J; Vestergaard, Henrik; Turner, Stephen T; Torp-Pedersen, Christian; Stergiakouli, Evie; Sheu, Wayne Huey-Herng; Rosendaal, Frits R; Ikram, M Arfan; Franco, Oscar H; Ridker, Paul M; Perls, Thomas T; Pedersen, Oluf; Nohr, Ellen A; Newman, Anne B; Linneberg, Allan; Langenberg, Claudia; Kilpeläinen, Tuomas O; Kardia, Sharon L R; Jørgensen, Marit E; Jørgensen, Torben; Sørensen, Thorkild I A; Homuth, Georg; Hansen, Torben; Goodarzi, Mark O; Deary, Ian J; Christensen, Cramer; Chen, Yii-Der Ida; Chakravarti, Aravinda; Brandslund, Ivan; Bonnelykke, Klaus; Taylor, Kent D; Wilson, James G; Rodriguez, Santiago; Davies, Gail; Horta, Bernardo L; Thyagarajan, Bharat; Rao, D C; Grarup, Niels; Davila-Roman, Victor G; Hudson, Gavin; Guo, Xiuqing; Arnett, Donna K; Hayward, Caroline; Vaidya, Dhananjay; Mook-Kanamori, Dennis O; Tiwari, Hemant K; Levy, Daniel; Loos, Ruth J F; Dehghan, Abbas; Elliott, Paul; Malik, Afshan N; Scott, Robert A; Becker, Diane M; de Andrade, Mariza; Province, Michael A; Meigs, James B; Rotter, Jerome I; North, Kari E
Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
PMCID:6323610
PMID: 30595373
ISSN: 1537-6605
CID: 3975012
Publisher Correction: 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; de Borst, Martin H; de Geus, Eco J; 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
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.
PMID: 30429575
ISSN: 1546-1718
CID: 3975562
A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
Ashar, Foram N; Mitchell, Rebecca N; Albert, Christine M; Newton-Cheh, Christopher; Brody, Jennifer A; Müller-Nurasyid, Martina; Moes, Anna; Meitinger, Thomas; Mak, Angel; Huikuri, Heikki; Junttila, M Juhani; Goyette, Philippe; Pulit, Sara L; Pazoki, Raha; Tanck, Michael W; Blom, Marieke T; Zhao, XiaoQing; Havulinna, Aki S; Jabbari, Reza; Glinge, Charlotte; Tragante, Vinicius; Escher, Stefan A; Chakravarti, Aravinda; Ehret, Georg; Coresh, Josef; Li, Man; Prineas, Ronald J; Franco, Oscar H; Kwok, Pui-Yan; Lumley, Thomas; Dumas, Florence; McKnight, Barbara; Rotter, Jerome I; Lemaitre, Rozenn N; Heckbert, Susan R; O'Donnell, Christopher J; Hwang, Shih-Jen; Tardif, Jean-Claude; VanDenburgh, Martin; Uitterlinden, André G; Hofman, Albert; Stricker, Bruno H C; de Bakker, Paul I W; Franks, Paul W; Jansson, Jan-Hakan; Asselbergs, Folkert W; Halushka, Marc K; Maleszewski, Joseph J; Tfelt-Hansen, Jacob; Engstrøm, Thomas; Salomaa, Veikko; Virmani, Renu; Kolodgie, Frank; Wilde, Arthur A M; Tan, Hanno L; Bezzina, Connie R; Eijgelsheim, Mark; Rioux, John D; Jouven, Xavier; Kääb, Stefan; Psaty, Bruce M; Siscovick, David S; Arking, Dan E; Sotoodehnia, Nona
Aims/UNASSIGNED:Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results/UNASSIGNED:We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25Â 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions/UNASSIGNED:Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
PMCID:6247663
PMID: 30169657
ISSN: 1522-9645
CID: 3657532
Response to Brosens et al
Jiang, Qian; Chen, Xiaoli; Zhang, Feng; Chakravarti, Aravinda; Li, Long
PMID: 29493585
ISSN: 1530-0366
CID: 3141622
Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants
Lee, Dongwon; Kapoor, Ashish; Safi, Alexias; Song, Lingyun; Halushka, Marc K; Crawford, Gregory E; Chakravarti, Aravinda
cis-regulatory elements (CRE), short DNA sequences through which transcription factors (TF) exert regulatory control on gene expression, are postulated to be the major sites of causal sequence variation underlying the genetics of complex traits and diseases. We present integrative analyses, combining high-throughput genomic and epigenomic data with sequence-based computations, to identify the causal transcriptional components in a given tissue. We use data on adult human hearts to demonstrate that a) sequence-based predictions detect numerous, active, tissue-specific CREs missed by experimental observations, b) learned sequence features identify the cognate TFs, c) CRE variants are specifically associated with cardiac gene expression, and, d) a significant fraction of the heritability of exemplar cardiac traits (QT interval, blood pressure, pulse rate) is attributable to these variants. This general systems approach can thus identify candidate causal variants and the components of gene regulatory networks (GRN) to enable understanding of the mechanisms of complex disorders at a tissue or cell-type basis.
PMID: 30139769
ISSN: 1549-5469
CID: 3246552
