Searched for: in-biosketch:yes
person:chakra01
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
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
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
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
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
Response to Brosens et al
Jiang, Qian; Chen, Xiaoli; Zhang, Feng; Chakravarti, Aravinda; Li, Long
PMID: 29493585
ISSN: 1530-0366
CID: 3141622
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
