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Ellinor, Patrick

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Ellinor

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Patrick

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Ellinor, Patrick

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    Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
    (Springer Science and Business Media LLC, 2021-06) Zekavat, Seyedeh M.; Lin, Shu-Hong; Bick, Alexander G.; Liu, Aoxing; Paruchuri, Kaavya; Wang, Chen; Uddin, Md Mesbah; Ye, Yixuan; Yu, Zhaolong; Liu, Xiaoxi; Kamatani, Yoichiro; Bhattacharya, Romit; Pirruccello, James; Pampana, Akhil; Loh, Po-Ru; Kohli, Puja; McCarroll, Steven; Kiryluk, Krzysztof; Neale, Benjamin; Ionita-Laza, Iuliana; Engels, Eric; Brown, Derek W.; Smoller, Jordan; Green, Robert; Karlson, Elizabeth; Lebo, Matthew; Ellinor, Patrick; Weiss, Scott; Daly, Mark; Terao, Chikashi; Zhao, Hongyu; Ebert, Benjamin; Reilly, Muredach; Ganna, Andrea; Machiela, Mitchell; Genovese, Giulio; Natarajan, Pradeep
    The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia. Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 x 10(-7)), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 x 10(-28)), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 x 10(-15)), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 x 10(-9)) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 x 10(-4)). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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    Relations of Liver Fat With Prevalent and Incident Atrial Fibrillation in the Framingham Heart Study
    (John Wiley and Sons Inc., 2017) Long, Michelle T.; Yin, Xiaoyan; Larson, Martin G.; Ellinor, Patrick; Lubitz, Steven; McManus, David D.; Magnani, Jared W.; Staerk, Laila; Ko, Darae; Helm, Robert H.; Hoffmann, Udo; Chung, Raymond; Benjamin, Emelia J.
    Background: Obesity is an important risk factor for nonalcoholic fatty liver disease and atrial fibrillation (AF). Less is known about the relations between nonalcoholic fatty liver disease and AF. We sought to evaluate the association between fatty liver and prevalent and incident AF in the community. Methods and Results: We examined Framingham Heart Study participants who underwent a study‐directed computed tomography scan, had hepatic steatosis (HS) evaluated, and did not report heavy alcohol use between 2002 and 2005. We evaluated cross‐sectional associations between liver fat and prevalent AF with logistic regression models. We assessed the relations between liver fat and incident AF during 12‐year follow‐up with Cox proportional hazards models. Of 2122 participants (53% women; mean age, 59.0±9.6 years), 20% had HS. AF prevalence (n=62) among individuals with HS was 4% compared to 3% among those without HS. There was no significant association between HS (measured as continuous or dichotomous variables) and prevalent AF in age‐ and sex‐adjusted or multivariable‐adjusted models. Incidence of AF (n=153) among participants with and without HS was 8.7 cases and 7.8 cases per 1000 person‐years, respectively. In age‐ and sex‐adjusted and multivariable‐adjusted models, there were no significant associations between continuous or dichotomous measures of HS and incident AF. Conclusions: In our community‐based, longitudinal cohort study, liver fat by computed tomography scan was not significantly associated with increased prevalence or incidence of AF over 12 years of follow‐up.
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    Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci
    (National Academy of Sciences, 2017) Lessard, Samuel; Francioli, Laurent; Alfoldi, Jessica; Tardif, Jean-Claude; Ellinor, Patrick; MacArthur, Daniel; Lettre, Guillaume; Orkin, Stuart; Canver, Matthew C.
    The CRISPR-Cas9 nuclease system holds enormous potential for therapeutic genome editing of a wide spectrum of diseases. Large efforts have been made to further understanding of on- and off-target activity to assist the design of CRISPR-based therapies with optimized efficacy and safety. However, current efforts have largely focused on the reference genome or the genome of cell lines to evaluate guide RNA (gRNA) efficiency, safety, and toxicity. Here, we examine the effect of human genetic variation on both on- and off-target specificity. Specifically, we utilize 7,444 whole-genome sequences to examine the effect of variants on the targeting specificity of ∼3,000 gRNAs across 30 therapeutically implicated loci. We demonstrate that human genetic variation can alter the off-target landscape genome-wide including creating and destroying protospacer adjacent motifs (PAMs). Furthermore, single-nucleotide polymorphisms (SNPs) and insertions/deletions (indels) can result in altered on-target sites and novel potent off-target sites, which can predispose patients to treatment failure and adverse effects, respectively; however, these events are rare. Taken together, these data highlight the importance of considering individual genomes for therapeutic genome-editing applications for the design and evaluation of CRISPR-based therapies to minimize risk of treatment failure and/or adverse outcomes.
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    Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium
    (Nature Publishing Group UK, 2017) Weng, Lu-Chen; Lunetta, Kathryn L.; Müller-Nurasyid, Martina; Smith, Albert Vernon; Thériault, Sébastien; Weeke, Peter E.; Barnard, John; Bis, Joshua C.; Lyytikäinen, Leo-Pekka; Kleber, Marcus E.; Martinsson, Andreas; Lin, Henry J.; Rienstra, Michiel; Trompet, Stella; Krijthe, Bouwe P.; Dörr, Marcus; Klarin, Derek; Chasman, Daniel; Sinner, Moritz F.; Waldenberger, Melanie; Launer, Lenore J.; Harris, Tamara B.; Soliman, Elsayed Z.; Alonso, Alvaro; Paré, Guillaume; Teixeira, Pedro L.; Denny, Joshua C.; Shoemaker, M. Benjamin; Van Wagoner, David R.; Smith, Jonathan D.; Psaty, Bruce M.; Sotoodehnia, Nona; Taylor, Kent D.; Kähönen, Mika; Nikus, Kjell; Delgado, Graciela E.; Melander, Olle; Engström, Gunnar; Yao, Jie; Guo, Xiuqing; Christophersen, Ingrid E.; Ellinor, Patrick; Geelhoed, Bastiaan; Verweij, Niek; Macfarlane, Peter; Ford, Ian; Heeringa, Jan; Franco, Oscar H.; Uitterlinden, André G.; Völker, Uwe; Teumer, Alexander; Rose, Lynda M.; Kääb, Stefan; Gudnason, Vilmundur; Arking, Dan E.; Conen, David; Roden, Dan M.; Chung, Mina K.; Heckbert, Susan R.; Benjamin, Emelia J.; Lehtimäki, Terho; März, Winfried; Smith, J. Gustav; Rotter, Jerome I.; van der Harst, Pim; Jukema, J. Wouter; Stricker, Bruno H.; Felix, Stephan B.; Albert, Christine; Lubitz, Steven
    It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10−5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10−8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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    Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity
    (2018) Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas GD; Manning, Alisa; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Heijer, Martin; den Hollander, Anneke I; den Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I. Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken Sin; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O’Donoghue, Michelle L.; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert Vernon; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; van der Laan, Sander W; van Duijn, Cornelia M; van Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel; Loos, Ruth JF
    Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity.
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    An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
    (Nature Publishing Group UK, 2018) Lino Cardenas, Christian; Kessinger, Chase; Cheng, Yisha; MacDonald, Carolyn; MacGillivray, Thomas; Ghoshhajra, Brian; Huleihel, Luai; Nuri, Saifar; Yeri, Ashish; Jaffer, Farouc; Kaminski, Naftali; Ellinor, Patrick; Weintraub, Neal L.; Malhotra, Rajeev; Isselbacher, Eric; Lindsay, Mark
    Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9–MALAT1–BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
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    Rare and low-frequency coding variants alter human adult height
    (2016) Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R; Kjaer, Troels R; Fine, Rebecca; Lu, Yingchang; Schurmann, Claudia; Highland, Heather M; Rüeger, Sina; Thorleifsson, Gudmar; Justice, Anne E; Lamparter, David; Stirrups, Kathleen E; Turcot, Valérie; Young, Kristin L; Winkler, Thomas W; Esko, Tõnu; Karaderi, Tugce; Locke, Adam E; Masca, Nicholas GD; Ng, Maggie CY; Mudgal, Poorva; Rivas, Manuel A; Vedantam, Sailaja; Mahajan, Anubha; Guo, Xiuqing; Abecasis, Goncalo; Aben, Katja K; Adair, Linda S; Alam, Dewan S; Albrecht, Eva; Allin, Kristine H; Allison, Matthew; Amouyel, Philippe; Appel, Emil V; Arveiler, Dominique; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Banas, Bernhard; Bang, Lia E; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bonnycastle, Lori L; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Burt, Amber A; Butterworth, Adam S; Carey, David J; Caulfield, Mark J; Chambers, John C; Chasman, Daniel; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Cuellar-Partida, Gabriel; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Borst, Gert J.; de Denus, Simon; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Hollander, Anneke I; Dennis, Joe G; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dunning, Alison M; Easton, Douglas F; Ebeling, Tapani; Edwards, Todd L; Ellinor, Patrick; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Faul, Jessica D; Feitosa, Mary F; Feng, Shuang; Ferrannini, Ele; Ferrario, Marco M; Ferrieres, Jean; Florez, Jose; Ford, Ian; Fornage, Myriam; Franks, Paul; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Giri, Ayush; Girotto, Giorgia; Gordon, Scott D; Gordon-Larsen, Penny; Gorski, Mathias; Grarup, Niels; Grove, Megan L.; Gudnason, Vilmundur; Gustafsson, Stefan; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Hayward, Caroline; He, Liang; Heid, Iris M; Heikkilä, Kauko; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Hocking, Lynne J; Hollensted, Mette; Holmen, Oddgeir L; Hovingh, G. Kees; Howson, Joanna MM; Hoyng, Carel B; Huang, Paul; Hveem, Kristian; Ikram, M. Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jhun, Min A; Jia, Yucheng; Jiang, Xuejuan; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jousilahti, Pekka; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kee, Frank; Keeman, Renske; Kiemeney, Lambertus A; Kitajima, Hidetoshi; Kluivers, Kirsten B; Kocher, Thomas; Komulainen, Pirjo; Kontto, Jukka; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kriebel, Jennifer; Kuivaniemi, Helena; Küry, Sébastien; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lakka, Timo A; Lange, Ethan M; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Larson, Eric B; Lee, I-Te; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Yeheng; Liu, Yongmei; Lophatananon, Artitaya; Luan, Jian'an; Lubitz, Steven; Lyytikäinen, Leo-Pekka; Mackey, David A; Madden, Pamela AF; Manning, Alisa; Männistö, Satu; Marenne, Gaëlle; Marten, Jonathan; Martin, Nicholas G; Mazul, Angela L; Meidtner, Karina; Metspalu, Andres; Mitchell, Paul; Mohlke, Karen L; Mook-Kanamori, Dennis O; Morgan, Anna; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Ntalla, Ioanna; O'Connel, Jeffrey R; Oksa, Heikki; Loohuis, Loes M Olde; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Pasterkamp, Gerard; Patel, Aniruddh; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R.B.; Person, Thomas N; Pirie, Ailith; Polasek, Ozren; Posthuma, Danielle; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Reiner, Alex P; Renström, Frida; Ridker, Paul; Rioux, John D; Robertson, Neil; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sandow, Kevin; Sapkota, Yadav; Sattar, Naveed; Schmidt, Marjanka K; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; Smith, Albert Vernon; Smith, Jennifer A; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Steinthorsdottir, Valgerdur; Stringham, Heather M; Stumvoll, Michael; Surendran, Praveen; Hart, Leen M ‘t; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Ulivi, Sheila; van der Laan, Sander W; Van Der Leij, Andries R; van Duijn, Cornelia M; van Schoor, Natasja M; van Setten, Jessica; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Edwards, Digna R Velez; Vermeulen, Sita H; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Vozzi, Diego; Walker, Mark; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Wareham, Nicholas J; Warren, Helen R; Wessel, Jennifer; Willems, Sara M; Wilson, James G; Witte, Daniel R; Woods, Michael O; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zheng, He; Zhou, Wei; Rotter, Jerome I; Boehnke, Michael; Kathiresan, Sekar; McCarthy, Mark I; Willer, Cristen J; Stefansson, Kari; Borecki, Ingrid B; Liu, Dajiang J; North, Kari E; Heard-Costa, Nancy L; Pers, Tune H; Lindgren, Cecilia M; Oxvig, Claus; Kutalik, Zoltán; Rivadeneira, Fernando; Loos, Ruth JF; Frayling, Timothy M; Hirschhorn, Joel; Deloukas, Panos; Lettre, Guillaume
    Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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    Association Between Leukocyte Telomere Length and the Risk of Incident Atrial Fibrillation: The Framingham Heart Study
    (John Wiley and Sons Inc., 2017) Staerk, Laila; Wang, Biqi; Lunetta, Kathryn L.; Helm, Robert H.; Ko, Darae; Sherer, Jason A.; Ellinor, Patrick; Lubitz, Steven; McManus, David D.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Trinquart, Ludovic
    Background: Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length (LTL) and incident AF. Methods and Results: We included AF‐free participants from the observational Framingham Heart Study Offspring cohort from 1995 to 1998, who had LTL measurements. We examined the association between baseline LTL and incident AF with multivariable Cox models adjusted for age, sex, current smoking, height, weight, systolic and diastolic blood pressure, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction, and history of heart failure. The study sample comprised 1143 AF‐free participants (52.8% women), with mean age of 60±8 years. The mean LTL at baseline was 6.95±0.57 kb. During 15.1±4.2 years mean follow‐up, 184 participants (64 women) developed AF. Chronological age was associated with increased risk of AF (hazard ratio per 10‐year increase, 2.16; 95% confidence interval, 1.71–2.72). There was no significant association between LTL and incident AF (hazard ratio per 1 SD decrease LTL, 1.01; 95% confidence interval, 0.86–1.19). Our study was observational in nature; hence, we could not exclude residual confounding and we were unable to establish causal pathways. Conclusions: In our moderate‐sized community‐based cohort, we did not find evidence for a significant association between LTL and risk of incident AF.
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    Whole Blood Gene Expression and Atrial Fibrillation: The Framingham Heart Study
    (Public Library of Science, 2014) Lin, Honghuang; Yin, Xiaoyan; Lunetta, Kathryn L.; Dupuis, Josée; McManus, David D.; Lubitz, Steven; Magnani, Jared W.; Joehanes, Roby; Munson, Peter J.; Larson, Martin G.; Levy, Daniel; Ellinor, Patrick; Benjamin, Emelia J.
    Background: Atrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF. Methods and Results: We performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66±9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8×10−7), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF. Conclusion: We examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation.
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    PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance
    (Public Library of Science, 2016) Kiando, Soto Romuald; Tucker, Nathan; Castro-Vega, Luis-Jaime; Katz, Alexander; D’Escamard, Valentina; Tréard, Cyrielle; Fraher, Daniel; Albuisson, Juliette; Kadian-Dodov, Daniella; Ye, Zi; Austin, Erin; Yang, Min-Lee; Hunker, Kristina; Barlassina, Cristina; Cusi, Daniele; Galan, Pilar; Empana, Jean-Philippe; Jouven, Xavier; Gimenez-Roqueplo, Anne-Paule; Bruneval, Patrick; Hyun Kim, Esther Soo; Olin, Jeffrey W.; Gornik, Heather L.; Azizi, Michel; Plouin, Pierre-François; Ellinor, Patrick; Kullo, Iftikhar J.; Milan, David; Ganesh, Santhi K.; Boutouyrie, Pierre; Kovacic, Jason C.; Jeunemaitre, Xavier; Bouatia-Naji, Nabila
    Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.