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151. A Comparison of Interactional Aerodynamics Methods for a Helicopter in Low Speed Flight

Author

Berry, John D, Letnikov, Victor, Bavykina, Irena, and Chaffin, Mark S

Subjects
Aircraft Design, Testing And Performance
Abstract

Recent advances in computing subsonic flow have been applied to helicopter configurations with various degrees of success. This paper is a comparison of two specific methods applied to a particularly challenging regime of helicopter flight, very low speeds, where the interaction of the rotor wake and the fuselage are most significant. Comparisons are made between different methods of predicting the interactional aerodynamics associated with a simple generic helicopter configuration. These comparisons are made using fuselage pressure data from a Mach-scaled powered model helicopter with a rotor diameter of approximately 3 meters. The data shown are for an advance ratio of 0.05 with a thrust coefficient of 0.0066. The results of this comparison show that in this type of complex flow both analytical techniques have regions where they are more accurate in matching the experimental data.

Published
1997

152. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Author

Natarajan, Pradeep, Natarajan, Pradeep, Peloso, Gina M, Zekavat, Seyedeh Maryam, Montasser, May, Ganna, Andrea, Chaffin, Mark, Khera, Amit V, Zhou, Wei, Bloom, Jonathan M, Engreitz, Jesse M, Ernst, Jason, O'Connell, Jeffrey R, Ruotsalainen, Sanni E, Alver, Maris, Manichaikul, Ani, Johnson, W Craig, Perry, James A, Poterba, Timothy, Seed, Cotton, Surakka, Ida L, Esko, Tonu, Ripatti, Samuli, Salomaa, Veikko, Correa, Adolfo, Vasan, Ramachandran S, Kellis, Manolis, Neale, Benjamin M, Lander, Eric S, Abecasis, Goncalo, Mitchell, Braxton, Rich, Stephen S, Wilson, James G, Cupples, L Adrienne, Rotter, Jerome I, Willer, Cristen J, Kathiresan, Sekar, NHLBI TOPMed Lipids Working Group, Natarajan, Pradeep, Natarajan, Pradeep, Peloso, Gina M, Zekavat, Seyedeh Maryam, Montasser, May, Ganna, Andrea, Chaffin, Mark, Khera, Amit V, Zhou, Wei, Bloom, Jonathan M, Engreitz, Jesse M, Ernst, Jason, O'Connell, Jeffrey R, Ruotsalainen, Sanni E, Alver, Maris, Manichaikul, Ani, Johnson, W Craig, Perry, James A, Poterba, Timothy, Seed, Cotton, Surakka, Ida L, Esko, Tonu, Ripatti, Samuli, Salomaa, Veikko, Correa, Adolfo, Vasan, Ramachandran S, Kellis, Manolis, Neale, Benjamin M, Lander, Eric S, Abecasis, Goncalo, Mitchell, Braxton, Rich, Stephen S, Wilson, James G, Cupples, L Adrienne, Rotter, Jerome I, Willer, Cristen J, Kathiresan, Sekar, and NHLBI TOPMed Lipids Working Group

Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Published
2018

153. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Author

Zekavat, Seyedeh M, Zekavat, Seyedeh M, Ruotsalainen, Sanni, Handsaker, Robert E, Alver, Maris, Bloom, Jonathan, Poterba, Timothy, Seed, Cotton, Ernst, Jason, Chaffin, Mark, Engreitz, Jesse, Peloso, Gina M, Manichaikul, Ani, Yang, Chaojie, Ryan, Kathleen A, Fu, Mao, Johnson, W Craig, Tsai, Michael, Budoff, Matthew, Vasan, Ramachandran S, Cupples, L Adrienne, Rotter, Jerome I, Rich, Stephen S, Post, Wendy, Mitchell, Braxton D, Correa, Adolfo, Metspalu, Andres, Wilson, James G, Salomaa, Veikko, Kellis, Manolis, Daly, Mark J, Neale, Benjamin M, McCarroll, Steven, Surakka, Ida, Esko, Tonu, Ganna, Andrea, Ripatti, Samuli, Kathiresan, Sekar, Natarajan, Pradeep, NHLBI TOPMed Lipids Working Group, Zekavat, Seyedeh M, Zekavat, Seyedeh M, Ruotsalainen, Sanni, Handsaker, Robert E, Alver, Maris, Bloom, Jonathan, Poterba, Timothy, Seed, Cotton, Ernst, Jason, Chaffin, Mark, Engreitz, Jesse, Peloso, Gina M, Manichaikul, Ani, Yang, Chaojie, Ryan, Kathleen A, Fu, Mao, Johnson, W Craig, Tsai, Michael, Budoff, Matthew, Vasan, Ramachandran S, Cupples, L Adrienne, Rotter, Jerome I, Rich, Stephen S, Post, Wendy, Mitchell, Braxton D, Correa, Adolfo, Metspalu, Andres, Wilson, James G, Salomaa, Veikko, Kellis, Manolis, Daly, Mark J, Neale, Benjamin M, McCarroll, Steven, Surakka, Ida, Esko, Tonu, Ganna, Andrea, Ripatti, Samuli, Kathiresan, Sekar, Natarajan, Pradeep, and NHLBI TOPMed Lipids Working Group

Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Published
2018

154. Multi-ethnic genome-wide association study for atrial fibrillation.

Author

Roselli, Carolina, Roselli, Carolina, Chaffin, Mark, Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine, Almgren, Peter, Alonso, Alvaro, Anderson, Christopher, Aragam, Krishna, Arking, Dan, Barnard, John, Bartz, Traci, Benjamin, Emelia, Bihlmeyer, Nathan, Bis, Joshua, Bloom, Heather, Boerwinkle, Eric, Bottinger, Erwin, Brody, Jennifer, Calkins, Hugh, Campbell, Archie, Cappola, Thomas, Carlquist, John, Chasman, Daniel, Chen, Lin, Chen, Yii-Der, Choi, Eue-Keun, Choi, Seung, Christophersen, Ingrid, Chung, Mina, Cole, John, Conen, David, Cook, James, Crijns, Harry, Cutler, Michael, Damrauer, Scott, Daniels, Brian, Darbar, Dawood, Delgado, Graciela, Denny, Joshua, Dichgans, Martin, Dörr, Marcus, Dudink, Elton, Dudley, Samuel, Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan, Ford, Ian, Franco, Oscar, Geelhoed, Bastiaan, Grewal, Raji, Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara, Hayward, Caroline, Heckbert, Susan, Hernesniemi, Jussi, Hocking, Lynne, Hofman, Albert, Horimoto, Andrea, Huang, Jie, Huang, Paul, Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J, Kääb, Stefan, Kähönen, Mika, Kamatani, Yoichiro, Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas, Kirchhof, Paulus, Kleber, Marcus, Knight, Stacey, Krieger, Jose, Kubo, Michiaki, Launer, Lenore, Laurikka, Jari, Lehtimäki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn, Li, Man, Lim, Hong, Lin, Henry, Lin, Honghuang, Lind, Lars, Roselli, Carolina, Roselli, Carolina, Chaffin, Mark, Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine, Almgren, Peter, Alonso, Alvaro, Anderson, Christopher, Aragam, Krishna, Arking, Dan, Barnard, John, Bartz, Traci, Benjamin, Emelia, Bihlmeyer, Nathan, Bis, Joshua, Bloom, Heather, Boerwinkle, Eric, Bottinger, Erwin, Brody, Jennifer, Calkins, Hugh, Campbell, Archie, Cappola, Thomas, Carlquist, John, Chasman, Daniel, Chen, Lin, Chen, Yii-Der, Choi, Eue-Keun, Choi, Seung, Christophersen, Ingrid, Chung, Mina, Cole, John, Conen, David, Cook, James, Crijns, Harry, Cutler, Michael, Damrauer, Scott, Daniels, Brian, Darbar, Dawood, Delgado, Graciela, Denny, Joshua, Dichgans, Martin, Dörr, Marcus, Dudink, Elton, Dudley, Samuel, Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan, Ford, Ian, Franco, Oscar, Geelhoed, Bastiaan, Grewal, Raji, Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara, Hayward, Caroline, Heckbert, Susan, Hernesniemi, Jussi, Hocking, Lynne, Hofman, Albert, Horimoto, Andrea, Huang, Jie, Huang, Paul, Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J, Kääb, Stefan, Kähönen, Mika, Kamatani, Yoichiro, Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas, Kirchhof, Paulus, Kleber, Marcus, Knight, Stacey, Krieger, Jose, Kubo, Michiaki, Launer, Lenore, Laurikka, Jari, Lehtimäki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn, Li, Man, Lim, Hong, Lin, Henry, Lin, Honghuang, and Lind, Lars

Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018

155. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Author

Emdin, Connor A, Emdin, Connor A, Khera, Amit V, Chaffin, Mark, Klarin, Derek, Natarajan, Pradeep, Aragam, Krishna, Haas, Mary, Bick, Alexander, Zekavat, Seyedeh M, Nomura, Akihiro, Ardissino, Diego, Wilson, James G, Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J, Samani, Nilesh J, Baber, Usman, Erdmann, Jeanette, Gupta, Namrata, Danesh, John, Chasman, Daniel, Ridker, Paul, Denny, Joshua, Bastarache, Lisa, Lichtman, Judith H, D'Onofrio, Gail, Mattera, Jennifer, Spertus, John A, Sheu, Wayne H-H, Taylor, Kent D, Psaty, Bruce M, Rich, Stephen S, Post, Wendy, Rotter, Jerome I, Chen, Yii-Der Ida, Krumholz, Harlan, Saleheen, Danish, Gabriel, Stacey, Kathiresan, Sekar, Emdin, Connor A, Emdin, Connor A, Khera, Amit V, Chaffin, Mark, Klarin, Derek, Natarajan, Pradeep, Aragam, Krishna, Haas, Mary, Bick, Alexander, Zekavat, Seyedeh M, Nomura, Akihiro, Ardissino, Diego, Wilson, James G, Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J, Samani, Nilesh J, Baber, Usman, Erdmann, Jeanette, Gupta, Namrata, Danesh, John, Chasman, Daniel, Ridker, Paul, Denny, Joshua, Bastarache, Lisa, Lichtman, Judith H, D'Onofrio, Gail, Mattera, Jennifer, Spertus, John A, Sheu, Wayne H-H, Taylor, Kent D, Psaty, Bruce M, Rich, Stephen S, Post, Wendy, Rotter, Jerome I, Chen, Yii-Der Ida, Krumholz, Harlan, Saleheen, Danish, Gabriel, Stacey, and Kathiresan, Sekar

Abstract

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

Published
2018

158. A guide to the use of the pressure disk rotor model as implemented in INS3D-UP

Author

Chaffin, Mark S

Subjects
Aerodynamics
Abstract

This is a guide for the use of the pressure disk rotor model that has been placed in the incompressible Navier-Stokes code INS3D-UP. The pressure disk rotor model approximates a helicopter rotor or propeller in a time averaged manner and is intended to simulate the effect of a rotor in forward flight on the fuselage or the effect of a propeller on other aerodynamic components. The model uses a modified actuator disk that allows the pressure jump across the disk to vary with radius and azimuth. The cyclic and collective blade pitch angles needed to achieve a specified thrust coefficient and zero moment about the hub are predicted. The method has been validated with experimentally measured mean induced inflow velocities as well as surface pressures on a generic fuselage. Overset grids, sometimes referred to as Chimera grids, are used to simplify the grid generation process. The pressure disk model is applied to a cylindrical grid which is embedded in the grid or grids used for the rest of the configuration. This document will outline the development of the method, and present input and results for a sample case.

Published
1995

159. Navier-Stokes and potential theory solutions for ahelicopter fuselage and comparison with experiment

Author

Chaffin, Mark S and Berry, John D

Subjects
Aerodynamics
Abstract

A thin-layer Navier-Stokes code and a panel method code are used to predict the flow over a generic helicopter fuselage. The computational results are compared with pressure data at four experimental conditions. Both methods produce results that agree with the experimental pressure data. However, separation patterns and other viscous flow features from the Navier-Stokes code solution are shown that cannot be easily modeled with the panel method.

Published
1994

160. Letters

Author

Heyman, David, Huff, James, Horwich, Ben, LaFountain, Marc, Hunter, Brian E., Eppick, Bill, Gibson, Earl H., Bailey, Jim, Chaffin, Mark A., Veloso, Manuel, Miller, Garner, and Aaronson, Dave

Abstract

Are you ready for the berdisk? David Carroll, of Brighton, Massachusetts, is. 'Instead of external megadrives spawning like fungi, why can't Fuji or Maxell simply foil all these entrepreneurs by […]

Published
1993

161. Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Christophersen, Ingrid E, Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E, Smith, Albert V, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A, Low, Siew-Kee, Weeke, Peter E, Müller-Nurasyid, Martina, Smith, J Gustav, Brody, Jennifer A, Niemeijer, Maartje N, Dörr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Malik, Rainer, R V R Horimoto, Andrea, Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Thériault, Sébastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J, Shah, Svati H, Sun, Albert, Hopewell, Jemma C, Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B, Paré, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P, Verweij, Niek, Siland, Joylene E, Kubo, Michiaki, Smith, Jonathan D, Van Wagoner, David R, Bis, Joshua C, Perz, Siegfried, Psaty, Bruce M, Ridker, Paul M, Magnani, Jared W, Harris, Tamara B, Launer, Lenore J, Shoemaker, M Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M, Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E, Kähönen, Mika, Risch, Lorenz, Mansur, Alfredo J, Peters, Annette, Smith, Blair H, Lind, Lars, Scott, Stuart A, Lu, Yingchang, Bottinger, Erwin B, Hernesniemi, Jussi, Lindgren, Cecilia M, Wong, Jorge A, Huang, Jie, Eskola, Markku, Morris, Andrew P, Ford, Ian, Reiner, Alex P, Delgado, Graciela, Chen, Lin Y, Chen, Yii-Der Ida, Sandhu, Roopinder K, Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D, Taylor, Kent D, Campbell, Archie, Magnusson, Patrik K, Porteous, David, Hocking, Lynne J, Vlachopoulou, Efthymia, Pedersen, Nancy L, Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C, Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W, Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L, Sotoodehnia, Nona, Soliman, Elsayed Z, Uitterlinden, Andre G, Hofman, Albert, Franco, Oscar H, Völker, Uwe, Jöckel, Karl-Heinz, Sinner, Moritz F, Lin, Henry J, Guo, Xiuqing, METASTROKE Consortium of the ISGC, Neurology Working Group of the CHARGE Consortium, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, J F Loos, Ruth, Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J Wouter, Hayward, Caroline, Rotter, Jerome I, März, Winfried, Lehtimäki, Terho, Stricker, Bruno H, Chung, Mina K, Felix, Stephan B, Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M, Kääb, Stefan, Chasman, Daniel I, Heckbert, Susan R, Benjamin, Emelia J, Tanaka, Toshihiro, Lunetta, Kathryn L, Lubitz, Steven A, Ellinor, Patrick T, and AFGen Consortium

Subjects
Genetics, Journal Article, Medizin, Article
Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death.1,2 Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups.3–7 To further define the genetic basis of atrial fibrillation, we performed large-scale, multi-racial meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 18,398 individuals with atrial fibrillation and 91,536 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,806 cases and 132,612 referents. We identified 12 novel genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate new potential targets for drug discovery.8

Published
2017

163. Transcriptional and Cellular Diversity of the Human Heart.

Author

Tucker, Nathan R., Chaffin, Mark, Fleming, Stephen J., Hall, Amelia W., Parsons, Victoria A., Bedi, Kenneth C., Akkad, Amer-Denis, Herndon, Caroline N., Arduini, Alessandro, Papangeli, Irinna, Roselli, Carolina, Aguet, François, Choi, Seung Hoan, Ardlie, Kristin G., Babadi, Mehrtash, Margulies, Kenneth B., Stegmann, Christian M., Ellinor, Patrick T., and Bedi, Kenneth C Jr

Subjects
*NUCLEOTIDE sequence, *HEART diseases, *HEART, *GENE expression, *EXTRACELLULAR matrix
Abstract

Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart.Methods: Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.Results: We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.Conclusions: Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Published
2020
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165. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author

Ntalla, Ioanna, Weng, Lu-Chen, Cartwright, James H., Hall, Amelia Weber, Sveinbjornsson, Gardar, Tucker, Nathan R., Choi, Seung Hoan, Chaffin, Mark D., Roselli, Carolina, Barnes, Michael R., Mifsud, Borbala, Warren, Helen R., Hayward, Caroline, Marten, Jonathan, Cranley, James J., Concas, Maria Pina, Gasparini, Paolo, Boutin, Thibaud, Kolcic, Ivana, and Polasek, Ozren

Subjects
MYOCARDIUM, ATRIAL fibrillation, DISEASE duration, CARDIOVASCULAR diseases, CARDIAC pacemakers, HERITABILITY, CARDIOMYOPATHIES
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci. [ABSTRACT FROM AUTHOR]

Published
2020
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166. Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.

Author

Pirruccello, James P., Bick, Alexander, Wang, Minxian, Chaffin, Mark, Friedman, Samuel, Yao, Jie, Guo, Xiuqing, Venkatesh, Bharath Ambale, Taylor, Kent D., Post, Wendy S., Rich, Stephen, Lima, Joao A. C., Rotter, Jerome I., Philippakis, Anthony, Lubitz, Steven A., Ellinor, Patrick T., Khera, Amit V., Kathiresan, Sekar, and Aragam, Krishna G.

Subjects
CARDIAC magnetic resonance imaging, DILATED cardiomyopathy, PATHOLOGY, HEART transplantation, HEART failure, NATALIZUMAB
Abstract

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM. Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM. [ABSTRACT FROM AUTHOR]

Published
2020
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167. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Author

Emdin, Connor A., Haas, Mary E., Khera, Amit V., Aragam, Krishna, Chaffin, Mark, Klarin, Derek, Hindy, George, Jiang, Lan, Wei, Wei-Qi, Feng, Qiping, Karjalainen, Juha, Havulinna, Aki, Kiiskinen, Tuomo, Bick, Alexander, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, and Elosua, Roberto

Subjects
LIVER diseases, BLOOD cholesterol, FATTY liver, ALANINE aminotransferase, LIVER enzymes, ALPHA 1-antitrypsin
Abstract

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis. Author summary: Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease. [ABSTRACT FROM AUTHOR]

Published
2020
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169. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Wilk, Jemma B., Morley, Michael P., Chaffin, Mark D., Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., and Bloom, Heather L.

Subjects
HEART failure, PATHOLOGY, CORONARY disease, HEART disease related mortality, ATRIAL fibrillation, BODY mass index
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported. [ABSTRACT FROM AUTHOR]

Published
2020
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170. DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

Author

Emdin, Connor A., primary, Khera, Amit V., additional, Aragam, Krishna, additional, Haas, Mary, additional, Chaffin, Mark, additional, Klarin, Derek, additional, Natarajan, Pradeep, additional, Bick, Alexander, additional, Zekavat, Seyedeh M., additional, Nomura, Akihiro, additional, Ardissino, Diego, additional, Wilson, James G., additional, Schunkert, Heribert, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Elosua, Roberto, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Baber, Usman, additional, Erdmann, Jeanette, additional, Gupta, Namrata, additional, Danesh, John, additional, Saleheen, Danish, additional, Gabriel, Stacey, additional, and Kathiresan, Sekar, additional

Published
2018
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171. Multi-ethnic genome-wide association study for atrial fibrillation

Author

Roselli, Carolina, primary, Chaffin, Mark D., additional, Weng, Lu-Chen, additional, Aeschbacher, Stefanie, additional, Ahlberg, Gustav, additional, Albert, Christine M., additional, Almgren, Peter, additional, Alonso, Alvaro, additional, Anderson, Christopher D., additional, Aragam, Krishna G., additional, Arking, Dan E., additional, Barnard, John, additional, Bartz, Traci M., additional, Benjamin, Emelia J., additional, Bihlmeyer, Nathan A., additional, Bis, Joshua C., additional, Bloom, Heather L., additional, Boerwinkle, Eric, additional, Bottinger, Erwin B., additional, Brody, Jennifer A., additional, Calkins, Hugh, additional, Campbell, Archie, additional, Cappola, Thomas P., additional, Carlquist, John, additional, Chasman, Daniel I., additional, Chen, Lin Y., additional, Chen, Yii-Der Ida, additional, Choi, Eue-Keun, additional, Choi, Seung Hoan, additional, Christophersen, Ingrid E., additional, Chung, Mina K., additional, Cole, John W., additional, Conen, David, additional, Cook, James, additional, Crijns, Harry J., additional, Cutler, Michael J., additional, Damrauer, Scott M., additional, Daniels, Brian R., additional, Darbar, Dawood, additional, Delgado, Graciela, additional, Denny, Joshua C., additional, Dichgans, Martin, additional, Dörr, Marcus, additional, Dudink, Elton A., additional, Dudley, Samuel C., additional, Esa, Nada, additional, Esko, Tonu, additional, Eskola, Markku, additional, Fatkin, Diane, additional, Felix, Stephan B., additional, Ford, Ian, additional, Franco, Oscar H., additional, Geelhoed, Bastiaan, additional, Grewal, Raji P., additional, Gudnason, Vilmundur, additional, Guo, Xiuqing, additional, Gupta, Namrata, additional, Gustafsson, Stefan, additional, Gutmann, Rebecca, additional, Hamsten, Anders, additional, Harris, Tamara B., additional, Hayward, Caroline, additional, Heckbert, Susan R., additional, Hernesniemi, Jussi, additional, Hocking, Lynne J., additional, Hofman, Albert, additional, Horimoto, Andrea R. V. R., additional, Huang, Jie, additional, Huang, Paul L., additional, Huffman, Jennifer, additional, Ingelsson, Erik, additional, Ipek, Esra Gucuk, additional, Ito, Kaoru, additional, Jimenez-Conde, Jordi, additional, Johnson, Renee, additional, Jukema, J. Wouter, additional, Kääb, Stefan, additional, Kähönen, Mika, additional, Kamatani, Yoichiro, additional, Kane, John P., additional, Kastrati, Adnan, additional, Kathiresan, Sekar, additional, Katschnig-Winter, Petra, additional, Kavousi, Maryam, additional, Kessler, Thorsten, additional, Kietselaer, Bas L., additional, Kirchhof, Paulus, additional, Kleber, Marcus E., additional, Knight, Stacey, additional, Krieger, Jose E., additional, Kubo, Michiaki, additional, Launer, Lenore J., additional, Laurikka, Jari, additional, Lehtimäki, Terho, additional, Leineweber, Kirsten, additional, Lemaitre, Rozenn N., additional, Li, Man, additional, Lim, Hong Euy, additional, Lin, Henry J., additional, Lin, Honghuang, additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Lokki, Marja-Liisa, additional, London, Barry, additional, Loos, Ruth J. F., additional, Low, Siew-Kee, additional, Lu, Yingchang, additional, Lyytikäinen, Leo-Pekka, additional, Macfarlane, Peter W., additional, Magnusson, Patrik K., additional, Mahajan, Anubha, additional, Malik, Rainer, additional, Mansur, Alfredo J., additional, Marcus, Gregory M., additional, Margolin, Lauren, additional, Margulies, Kenneth B., additional, März, Winfried, additional, McManus, David D., additional, Melander, Olle, additional, Mohanty, Sanghamitra, additional, Montgomery, Jay A., additional, Morley, Michael P., additional, Morris, Andrew P., additional, Müller-Nurasyid, Martina, additional, Natale, Andrea, additional, Nazarian, Saman, additional, Neumann, Benjamin, additional, Newton-Cheh, Christopher, additional, Niemeijer, Maartje N., additional, Nikus, Kjell, additional, Nilsson, Peter, additional, Noordam, Raymond, additional, Oellers, Heidi, additional, Olesen, Morten S., additional, Orho-Melander, Marju, additional, Padmanabhan, Sandosh, additional, Pak, Hui-Nam, additional, Paré, Guillaume, additional, Pedersen, Nancy L., additional, Pera, Joanna, additional, Pereira, Alexandre, additional, Porteous, David, additional, Psaty, Bruce M., additional, Pulit, Sara L., additional, Pullinger, Clive R., additional, Rader, Daniel J., additional, Refsgaard, Lena, additional, Ribasés, Marta, additional, Ridker, Paul M., additional, Rienstra, Michiel, additional, Risch, Lorenz, additional, Roden, Dan M., additional, Rosand, Jonathan, additional, Rosenberg, Michael A., additional, Rost, Natalia, additional, Rotter, Jerome I., additional, Saba, Samir, additional, Sandhu, Roopinder K., additional, Schnabel, Renate B., additional, Schramm, Katharina, additional, Schunkert, Heribert, additional, Schurman, Claudia, additional, Scott, Stuart A., additional, Seppälä, Ilkka, additional, Shaffer, Christian, additional, Shah, Svati, additional, Shalaby, Alaa A., additional, Shim, Jaemin, additional, Shoemaker, M. Benjamin, additional, Siland, Joylene E., additional, Sinisalo, Juha, additional, Sinner, Moritz F., additional, Slowik, Agnieszka, additional, Smith, Albert V., additional, Smith, Blair H., additional, Smith, J. Gustav, additional, Smith, Jonathan D., additional, Smith, Nicholas L., additional, Soliman, Elsayed Z., additional, Sotoodehnia, Nona, additional, Stricker, Bruno H., additional, Sun, Albert, additional, Sun, Han, additional, Svendsen, Jesper H., additional, Tanaka, Toshihiro, additional, Tanriverdi, Kahraman, additional, Taylor, Kent D., additional, Teder-Laving, Maris, additional, Teumer, Alexander, additional, Thériault, Sébastien, additional, Trompet, Stella, additional, Tucker, Nathan R., additional, Tveit, Arnljot, additional, Uitterlinden, Andre G., additional, Van Der Harst, Pim, additional, Van Gelder, Isabelle C., additional, Van Wagoner, David R., additional, Verweij, Niek, additional, Vlachopoulou, Efthymia, additional, Völker, Uwe, additional, Wang, Biqi, additional, Weeke, Peter E., additional, Weijs, Bob, additional, Weiss, Raul, additional, Weiss, Stefan, additional, Wells, Quinn S., additional, Wiggins, Kerri L., additional, Wong, Jorge A., additional, Woo, Daniel, additional, Worrall, Bradford B., additional, Yang, Pil-Sung, additional, Yao, Jie, additional, Yoneda, Zachary T., additional, Zeller, Tanja, additional, Zeng, Lingyao, additional, Lubitz, Steven A., additional, Lunetta, Kathryn L., additional, and Ellinor, Patrick T., additional

Published
2018
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172. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author

Emdin, Connor A., primary, Khera, Amit V., additional, Chaffin, Mark, additional, Klarin, Derek, additional, Natarajan, Pradeep, additional, Aragam, Krishna, additional, Haas, Mary, additional, Bick, Alexander, additional, Zekavat, Seyedeh M., additional, Nomura, Akihiro, additional, Ardissino, Diego, additional, Wilson, James G., additional, Schunkert, Heribert, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Elosua, Roberto, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Baber, Usman, additional, Erdmann, Jeanette, additional, Gupta, Namrata, additional, Danesh, John, additional, Chasman, Daniel, additional, Ridker, Paul, additional, Denny, Joshua, additional, Bastarache, Lisa, additional, Lichtman, Judith H., additional, D’Onofrio, Gail, additional, Mattera, Jennifer, additional, Spertus, John A., additional, Sheu, Wayne H.-H., additional, Taylor, Kent D., additional, Psaty, Bruce M., additional, Rich, Stephen S., additional, Post, Wendy, additional, Rotter, Jerome I., additional, Chen, Yii-Der Ida, additional, Krumholz, Harlan, additional, Saleheen, Danish, additional, Gabriel, Stacey, additional, and Kathiresan, Sekar, additional

Published
2018
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174. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Author

Muus, Christoph, Luecken, Malte D., Eraslan, Gökcen, Sikkema, Lisa, Waghray, Avinash, Heimberg, Graham, Kobayashi, Yoshihiko, Vaishnav, Eeshit Dhaval, Subramanian, Ayshwarya, Smillie, Christopher, Jagadeesh, Karthik A., Duong, Elizabeth Thu, Fiskin, Evgenij, Triglia, Elena Torlai, Ansari, Meshal, Cai, Peiwen, Lin, Brian, Buchanan, Justin, Chen, Sijia, Shu, Jian, Haber, Adam L., Chung, Hattie, Montoro, Daniel T., Adams, Taylor, Aliee, Hananeh, Allon, Samuel J., Andrusivova, Zaneta, Angelidis, Ilias, Ashenberg, Orr, Bassler, Kevin, Bécavin, Christophe, Benhar, Inbal, Bergenstråhle, Joseph, Bergenstråhle, Ludvig, Bolt, Liam, Braun, Emelie, Bui, Linh T., Callori, Steven, Chaffin, Mark, Chichelnitskiy, Evgeny, Chiou, Joshua, Conlon, Thomas M., Cuoco, Michael S., Cuomo, Anna S. E., Deprez, Marie, Duclos, Grant, Fine, Denise, Fischer, David S., Ghazanfar, Shila, Gillich, Astrid, Giotti, Bruno, Gould, Joshua, Guo, Minzhe, Gutierrez, Austin J., Habermann, Arun C., Harvey, Tyler, He, Peng, Hou, Xiaomeng, Hu, Lijuan, Hu, Yan, Jaiswal, Alok, Ji, Lu, Jiang, Peiyong, Kapellos, Theodoros S., Kuo, Christin S., Larsson, Ludvig, Leney-Greene, Michael A., Lim, Kyungtae, Litviňuková, Monika, Ludwig, Leif S., Lukassen, Soeren, Luo, Wendy, Maatz, Henrike, Madissoon, Elo, Mamanova, Lira, Manakongtreecheep, Kasidet, Leroy, Sylvie, Mayr, Christoph H., Mbano, Ian M., McAdams, Alexi M., Nabhan, Ahmad N., Nyquist, Sarah K., Penland, Lolita, Poirion, Olivier B., Poli, Sergio, Qi, CanCan, Queen, Rachel, Reichart, Daniel, Rosas, Ivan, Schupp, Jonas C., Shea, Conor V., Shi, Xingyi, Sinha, Rahul, Sit, Rene V., Slowikowski, Kamil, Slyper, Michal, Smith, Neal P., Sountoulidis, Alex, Strunz, Maximilian, Sullivan, Travis B., Sun, Dawei, Talavera-López, Carlos, Tan, Peng, Tantivit, Jessica, Travaglini, Kyle J., Tucker, Nathan R., Vernon, Katherine A., Wadsworth, Marc H., Waldman, Julia, Wang, Xiuting, Xu, Ke, Yan, Wenjun, Zhao, William, and Ziegler, Carly G. K.

Abstract

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2and CTSLacross 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2and CTSLare coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Published
2021
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175. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Christophersen, Ingrid E., Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E., Smith, Albert V., Albert, Christine M., Chaffin, Mark, Tucker, Nathan R., Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A., Low, Siew-Kee, Weeke, Peter E., Mueller-Nurasyid, Martina, Smith, J. Gustav, Brody, Jennifer A., Niemeijer, Maartje N., Doerr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E., Lyytikainen, Leo-Pekka, Seppala, Ilkka, Malik, Rainer, Horimoto, Andrea R. V. R., Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Theriault, Sebastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J., Shah, Svati H., Sun, Albert, Hopewell, Jemma C., Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B., Pare, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P., Verweij, Niek, Siland, Joylene E., Kubo, Michiaki, Smith, Jonathan D., Van Wagoner, David R., Bis, Joshua C., Perz, Siegfried, Psaty, Bruce M., Ridker, Paul M., Magnani, Jared W., Harris, Tamara B., Launer, Lenore J., Shoemaker, M. Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M., Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E., Kahonen, Mika, Risch, Lorenz, Mansur, Alfredo J., Peters, Annette, Smith, Blair H., Lind, Lars, Scott, Stuart A., Lu, Yingchang, Bottinger, Erwin B., Hernesniemi, Jussi, Lindgren, Cecilia M., Wong, Jorge A., Huang, Jie, Eskola, Markku, Morris, Andrew P., Ford, Ian, Reiner, Alex P., Delgado, Graciela, Chen, Lin Y., Chen, Yii-Der Ida, Sandhu, Roopinder K., Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D., Taylor, Kent D., Campbell, Archie, Magnusson, Patrik K., Porteous, David, Hocking, Lynne J., Vlachopoulou, Efthymia, Pedersen, Nancy L., Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C., Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W., Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L., Sotoodehnia, Nona, Soliman, Elsayed Z., Uitterlinden, Andre G., Hofman, Albert, Franco, Oscar H., Voelker, Uwe, Joeckel, Karl-Heinz, Sinner, Moritz F., Lin, Henry J., Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, Loos, Ruth J. F., Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J. Wouter, Hayward, Caroline, Rotter, Jerome I., Maerz, Winfried, Lehtimaki, Terho, Stricker, Bruno H., Chung, Mina K., Felix, Stephan B., Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M., Kaeaeb, Stefan, Chasman, Daniel I., Heckbert, Susan R., Benjamin, Emelia J., Tanaka, Toshihiro, Lunetta, Kathryn L., Lubitz, Steven A., Ellinor, Patrick T., Christophersen, Ingrid E., Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E., Smith, Albert V., Albert, Christine M., Chaffin, Mark, Tucker, Nathan R., Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A., Low, Siew-Kee, Weeke, Peter E., Mueller-Nurasyid, Martina, Smith, J. Gustav, Brody, Jennifer A., Niemeijer, Maartje N., Doerr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E., Lyytikainen, Leo-Pekka, Seppala, Ilkka, Malik, Rainer, Horimoto, Andrea R. V. R., Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Theriault, Sebastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J., Shah, Svati H., Sun, Albert, Hopewell, Jemma C., Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B., Pare, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P., Verweij, Niek, Siland, Joylene E., Kubo, Michiaki, Smith, Jonathan D., Van Wagoner, David R., Bis, Joshua C., Perz, Siegfried, Psaty, Bruce M., Ridker, Paul M., Magnani, Jared W., Harris, Tamara B., Launer, Lenore J., Shoemaker, M. Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M., Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E., Kahonen, Mika, Risch, Lorenz, Mansur, Alfredo J., Peters, Annette, Smith, Blair H., Lind, Lars, Scott, Stuart A., Lu, Yingchang, Bottinger, Erwin B., Hernesniemi, Jussi, Lindgren, Cecilia M., Wong, Jorge A., Huang, Jie, Eskola, Markku, Morris, Andrew P., Ford, Ian, Reiner, Alex P., Delgado, Graciela, Chen, Lin Y., Chen, Yii-Der Ida, Sandhu, Roopinder K., Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D., Taylor, Kent D., Campbell, Archie, Magnusson, Patrik K., Porteous, David, Hocking, Lynne J., Vlachopoulou, Efthymia, Pedersen, Nancy L., Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C., Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W., Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L., Sotoodehnia, Nona, Soliman, Elsayed Z., Uitterlinden, Andre G., Hofman, Albert, Franco, Oscar H., Voelker, Uwe, Joeckel, Karl-Heinz, Sinner, Moritz F., Lin, Henry J., Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, Loos, Ruth J. F., Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J. Wouter, Hayward, Caroline, Rotter, Jerome I., Maerz, Winfried, Lehtimaki, Terho, Stricker, Bruno H., Chung, Mina K., Felix, Stephan B., Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M., Kaeaeb, Stefan, Chasman, Daniel I., Heckbert, Susan R., Benjamin, Emelia J., Tanaka, Toshihiro, Lunetta, Kathryn L., Lubitz, Steven A., and Ellinor, Patrick T.

Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery(8).

Published
2017
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180. Abstract P100: Heritability of Atrial Fibrillation

Author

Weng, Lu-Chen, primary, Choi, Seung Hoan, additional, Klarin, Derek, additional, Loh, Po-Ru, additional, Chaffin, Mark, additional, Roselli, Carolina, additional, Hulme, Olivia, additional, Smith, J. Gustav, additional, Kathiresan, Sekar, additional, Lunetta, Kathryn, additional, Dupuis, Josée, additional, Newton-Cheh, Chris, additional, Benjamin, Emelia J, additional, Ellinor, Patrick T, additional, and Lubitz, Steven A, additional

Published
2017
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183. From a 'perfect storm' to 'smooth sailing': policymaker perspectives on implementation and sustainment of an evidence-based practice in two states

Author

Willging, Cathleen E, Green, Amy E, Gunderson, Lara, Chaffin, Mark, and Aarons, Gregory A

Subjects
Pediatric Research Initiative, Social Work, dissemination/implementation, Advisory Committees, evidence-based practice, Child Welfare, Family Studies, child welfare services/child protection, Clinical Research, Humans, Psychology, Child Abuse, Cooperative Behavior, Child, Policy Making, Prevention, Health Plan Implementation, Health Services, United States, Health Planning, Interinstitutional Relations, Good Health and Well Being, home visiting, Generic health relevance, child maltreatment, qualitative research
Abstract

Policymakers shape implementation and sustainment of evidence-based practices (EBPs), whether they are developing or responding to legislation and policies or negotiating public sector resource constraints. As part of a large mixed-method study, we conducted qualitative interviews with 24 policymakers involved in delivery of the same EBP in two U.S. states. We analyzed transcripts via open and focused coding techniques to identify the commonality, diversity, and complexity of implementation challenges; approaches to overcoming those challenges; and the importance of system-level contextual factors in ensuring successful implementation. Key findings centered on building support and leadership for EBPs; funding and contractual strategies; partnering with stakeholders; tackling challenges via proactive planning and problem solving; and the political, legal, and systemic pressures affecting EBP longevity. The policymaker perspectives offer guidance on nurturing system and organizational practice environments to achieve positive outcomes and for optimally addressing macro-level influences that bear upon the instantiation of EBPs in public sector child welfare systems.

Published
2015

184. Whole Genome Sequencing Identifies CRISPLD2as a Lung Function Gene in Children With Asthma

Author

Kachroo, Priyadarshini, Hecker, Julian, Chawes, Bo L., Ahluwalia, Tarunveer S., Cho, Michael H., Qiao, Dandi, Kelly, Rachel S., Chu, Su H., Virkud, Yamini V., Huang, Mengna, Barnes, Kathleen C., Burchard, Esteban G., Eng, Celeste, Hu, Donglei, Celedón, Juan C., Daya, Michelle, Levin, Albert M., Gui, Hongsheng, Williams, L. Keoki, Forno, Erick, Mak, Angel C.Y., Avila, Lydiana, Soto-Quiros, Manuel E., Cloutier, Michelle M., Acosta-Pérez, Edna, Canino, Glorisa, Bønnelykke, Klaus, Bisgaard, Hans, Raby, Benjamin A., Lange, Christoph, Weiss, Scott T., Lasky-Su, Jessica A., Abe, Namiko, Abecasis, Goncalo, Albert, Christine, Palmer Allred, Nicholette (Nichole), Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Arking, Dan, Arnett, Donna K., Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Beaty, Terri, Becker, Diane, Becker, Lewis, Beer, Rebecca, Begum, Ferdouse, Beitelshees, Amber, Benjamin, Emelia, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Boerwinkle, Eric, Borecki, Ingrid, Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Bunting, Karen, Burchard, Esteban, Cardwell, Jonathan, Carty, Cara, Casaburi, Richard, Casella, James, Chaffin, Mark, Chang, Christy, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Chen, Yii-Der Ida, Cho, Michael H., Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, Das, Sayantan, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Do, Ron, Duan, Qing, Duggirala, Ravi, Durda, Peter, Dutcher, Susan, Eaton, Charles, Ekunwe, Lynette, Ellinor, Patrick, Emery, Leslie, Farber, Charles, Farnam, Leanna, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Yan, Gass, Margery, Gelb, Bruce, Geng, Xiaoqi (Priscilla), Germer, Soren, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Haessler, Jeff, Hall, Michael, Harris, Daniel, Hawley, Nicola, He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hokanson, John, Holly, Kramer, Hong, Elliott, Hoth, Karin, (Agnes) Hsiung, Chao, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Jhun, Min A., Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kachroo, Priyadarshini, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kathiresan, Sekar, Kaufman, Laura, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Krauter, Stephanie, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Seunggeun Shawn, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Yun, Lin, Honghuang, Lin, Keng Han, Liu, Simin, Liu, Yongmei, Loos, Ruth, Lubitz, Steven, Lunetta, Kathryn, Luo, James, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manson, JoAnn, Margolin, Lauren, Martin, Lisa, Mathai, Susan, Mathias, Rasika, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, Mei, Hao, Meyers, Deborah A., Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L., Mitchell, Braxton, Montasser, May E., Musani, Solomon, Mwasongwe, Stanford, Mychaleckyj, Josyf C., Nadkarni, Girish, Naik, Rakhi, Natarajan, Pradeep, Nekhai, Sergei, Nickerson, Deborah, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Pankow, James, Papanicolaou, George, Parker, Margaret, Parsa, Afshin, Penchev, Sara, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S., Phillips, Sam, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Prokopenko, Dmitry, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Ramachandran, Vasan, Rao, D.C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Regan, Elizabeth, Reiner, Alex, Rice, Ken, Rich, Stephen, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sakornsakolpat, Phuwanat, Salimi, Shabnam, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay, Scheller, Christopher, Schmidt, Ellen, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sheehan, Vivien, Shetty, Amol, Shetty, Aniket, Sheu, Wayne Hui-Heng, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne, Streeten, Elizabeth, Sung, Yun Ju, Su-Lasky, Jessica, Sylvia, Jody, Szpiro, Adam, Sztalryd, Carole, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Tinker, Lesley, Tirschwell, David, Tiwari, Hemant, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wan, Emily, Wang, Fei Fei, Watson, Karol, Weeks, Daniel E., Weir, Bruce, Weiss, Scott, Weng, Lu-Chen, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Wong, Quenna, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yang, Rongze, Zaghloul, Norann, Zekavat, Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zheng, Xiuwen, Zhi, Degui, Zhou, Xiang, Zody, Michael, and Zoellner, Sebastian

Abstract

Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma.

Published
2019
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186. Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.

Author

Khera, Amit V., Chaffin, Mark, Zekavat, Seyedeh M., Collins, Ryan L., Roselli, Carolina, Natarajan, Pradeep, Lichtman, Judith H., D'Onofrio, Gail, Mattera, Jennifer, Dreyer, Rachel, Spertus, John A., Taylor, Kent D., Psaty, Bruce M., Rich, Stephen S., Post, Wendy, Gupta, Namrata, Gabriel, Stacey, Lander, Eric, Ida Chen, Yii-Der, and Talkowski, Michael E.

Subjects
*MYOCARDIAL infarction, *CLINICAL trial registries, *FAMILIAL hypercholesterolemia, *HYPERCHOLESTEREMIA
Abstract

Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).Conclusions: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922. [ABSTRACT FROM AUTHOR]

Published
2019
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189. DNA Sequence Variation in Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes.

Author

Emdin, Connor A., Khera, Amit V., Aragam, Krishna, Haas, Mary, Chaffin, Mark, Klarin, Derek, Natarajan, Pradeep, Bick, Alexander, Zekavat, Seyedeh M., Akihiro Nomura, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J., Samani, Nilesh J., Baber, Usman, and Erdmann, Jeanette

Subjects
NUCLEOTIDE sequencing, TYPE 2 diabetes, FAT, ADIPOSE tissues, ACTIVIN receptor-like kinase 1, ALGORITHMS, CELL receptors, COMPARATIVE studies, DISEASE susceptibility, GENOMES, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RESEARCH funding, EVALUATION research, SEQUENCE analysis
Abstract

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2019
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190. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Author

Choi, Seung Hoan, Weng, Lu-Chen, Roselli, Carolina, Lin, Honghuang, Haggerty, Christopher M., Shoemaker, M. Benjamin, Barnard, John, Arking, Dan E., Chasman, Daniel I., Albert, Christine M., Chaffin, Mark, Tucker, Nathan R., Smith, Jonathan D., Gupta, Namrata, Gabriel, Stacey, Margolin, Lauren, Shea, Marisa A., Shaffer, Christian M., Yoneda, Zachary T., and Boerwinkle, Eric

Abstract

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood.Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF.Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants).Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome.Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3.Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01).Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship. [ABSTRACT FROM AUTHOR]

Published
2018
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191. A genetic-association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Brody, Jennifer A., Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Jain, Deepti, Lewis, Joshua P., Rodriguez, Benjmain A. T., Pankratz, Nathan, Taylor, Kent D., Polasek, Ozren, Chen, Ming-Huei, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Ekunwe, Lynette, Davies, Gail, Delgado, Graciela E., Suchon, Pierre, Guo, Xiuqing, Rosendaal, Frits R., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Boerwinkle, Eric, Beswick, Andrew, Psaty, Bruce M., Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Deleuze, Jean-François, Rich, Stephen S., van Hylckama Vlieg, Astrid, Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Almasy, Laura, Brody, Lawrence C., Auer, Paul L., Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., Mitchell, Braxton D., Ben-Shlomo, Yoav, Fornage, Myriam, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Morange, Pierre-Emmanuel, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Blangero, John, Kooperberg, Charles, Desch, Karl C., Johnson, Andrew D., Sabater-Lleal, Maria, Lowenstein, Charles J., Smith, Nicholas L., and Morrison, Alanna C.

Abstract

•We identified 7 new genetic regions for factor VIII levels, 1 for von Willebrand factor levels, and 3 in a combined analysis.•Silencing B3GNT2and CD36reduced factor VIII release in vitro.Silencing B3GNT2, CD36, and PDIA3reduced von Willebrand factor release.

Published
2024
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193. Alcohol and HIV Risk Among Russian Women of Childbearing Age

Author

Balachova, Tatiana, primary, Shaboltas, Alla, additional, Nasledov, Andrey, additional, Chaffin, Mark, additional, Batluk, Julia, additional, Bohora, Som, additional, Bonner, Barbara, additional, Bryant, Kendall, additional, Tsvetkova, Larissa, additional, and Volkova, Elena, additional

Published
2016
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199. Myocyte-Specific Upregulation of in Cardiovascular Disease: Implications for SARS-CoV-2-Mediated Myocarditis.

Author

Tucker, Nathan R., Chaffin, Mark, Bedi, Kenneth C., Papangeli, Irinna, Akkad, Amer-Denis, Arduini, Alessandro, Hayat, Sikander, Eraslan, Gökcen, Muus, Christoph, Bhattacharyya, Roby P., Stegmann, Christian M., Margulies, Kenneth B., Ellinor, Patrick T., Bedi, Kenneth C Jr, Human Cell Atlas Lung Biological Network, and Human Cell Atlas Lung Biological Network Consortium Members

Subjects
*CARDIOVASCULAR diseases, *MYOCARDITIS
Abstract

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

Published
2020
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