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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
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
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
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
