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1. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O’Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno HC, de Bakker, Paul IW, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur AM, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, and Sotoodehnia, Nona

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Prevention, Heart Disease, Human Genome, Genetics, Clinical Research, Heart Disease - Coronary Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Arrhythmias, Cardiac, Body Mass Index, Coronary Artery Disease, Death, Sudden, Cardiac, Female, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Sex Factors, Sudden cardiac arrest, Genome-wide association study, Mendelian randomization, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

AimsSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and resultsWe carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Published
2018

2. Association of Mitochondrial DNA Copy Number With Cardiovascular Disease

Author

Ashar, Foram N, Zhang, Yiyi, Longchamps, Ryan J, Lane, John, Moes, Anna, Grove, Megan L, Mychaleckyj, Josyf C, Taylor, Kent D, Coresh, Josef, Rotter, Jerome I, Boerwinkle, Eric, Pankratz, Nathan, Guallar, Eliseo, and Arking, Dan E

Subjects
Heart Disease - Coronary Heart Disease, Cardiovascular, Heart Disease, Prevention, Atherosclerosis, Aging, Clinical Research, Genetics, Good Health and Well Being, Aged, Blood Buffy Coat, Cardiovascular Diseases, Cohort Studies, Coronary Disease, DNA, Mitochondrial, Female, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Proportional Hazards Models, Prospective Studies, Risk Assessment, United States
Abstract

ImportanceMitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.ObjectiveTo determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.Design, setting, and participantsProspective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.ExposuresMitochondrial DNA-CN measured from buffy coat/circulating leukocytes.Main outcomes and measuresIncident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.ResultsOf the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P

Published
2017

3. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author

Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O’Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t’Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, Woo, Daniel, and Rosand, Jonathan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis, Telomeres Mendelian Randomization Collaboration, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

4. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Author

Telomeres Mendelian Randomization Collaboration, Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t'Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, and Woo, Daniel

Subjects
Telomeres Mendelian Randomization Collaboration, Telomere, Humans, Neoplasms, Cardiovascular Diseases, Genetic Predisposition to Disease, Risk Assessment, Germ-Line Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Mendelian Randomization Analysis, Telomere Homeostasis, Polymorphism, Single Nucleotide, and over, Prevention, Clinical Research, Cancer, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

5. RNA-Seq optimization with eQTL gold standards.

Author

Ellis, Shannon E, Gupta, Simone, Ashar, Foram N, Bader, Joel S, West, Andrew B, and Arking, Dan E

Subjects
Brain, Blood, Humans, Reproducibility of Results, Chromosome Mapping, Sequence Analysis, RNA, Quantitative Trait Loci, Reference Standards, Genotyping Techniques, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics
Abstract

BackgroundRNA-Sequencing (RNA-Seq) experiments have been optimized for library preparation, mapping, and gene expression estimation. These methods, however, have revealed weaknesses in the next stages of analysis of differential expression, with results sensitive to systematic sample stratification or, in more extreme cases, to outliers. Further, a method to assess normalization and adjustment measures imposed on the data is lacking.ResultsTo address these issues, we utilize previously published eQTLs as a novel gold standard at the center of a framework that integrates DNA genotypes and RNA-Seq data to optimize analysis and aid in the understanding of genetic variation and gene expression. After detecting sample contamination and sequencing outliers in RNA-Seq data, a set of previously published brain eQTLs was used to determine if sample outlier removal was appropriate. Improved replication of known eQTLs supported removal of these samples in downstream analyses. eQTL replication was further employed to assess normalization methods, covariate inclusion, and gene annotation. This method was validated in an independent RNA-Seq blood data set from the GTEx project and a tissue-appropriate set of eQTLs. eQTL replication in both data sets highlights the necessity of accounting for unknown covariates in RNA-Seq data analysis.ConclusionAs each RNA-Seq experiment is unique with its own experiment-specific limitations, we offer an easily-implementable method that uses the replication of known eQTLs to guide each step in one's data analysis pipeline. In the two data sets presented herein, we highlight not only the necessity of careful outlier detection but also the need to account for unknown covariates in RNA-Seq experiments.

Published
2013

8. Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death

Author

Mitchell, Rebecca N., primary, Ashar, Foram N., additional, Jarvelin, Marjo‐Riitta, additional, Froguel, Philippe, additional, Sotoodehnia, Nona, additional, Brody, Jennifer A., additional, Sebert, Sylvain, additional, Huikuri, Heikki, additional, Rioux, John, additional, Goyette, Philippe, additional, Newcomb, Charles E., additional, Junttila, M. Juhani, additional, and Arking, Dan E., additional

Published
2019
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9. The effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death

Author

Mitchell, Rebecca N., primary, Ashar, Foram N., additional, Jarvelin, Marjo-Riitta, additional, Froguel, Philippe, additional, Sotoodehnia, Nona, additional, Brody, Jennifer A., additional, Sebert, Sylvain, additional, Huikuri, Heikki, additional, Rioux, John, additional, Goyette, Philippe, additional, Newcomb, Charles E., additional, Junttila, M. Juhani, additional, and Arking, Dan E., additional

Published
2019
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10. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Ashar, Foram N., Mitchell, Rebecca N., Albert, Christine M., Newton-Cheh, Christopher, Brody, Jennifer A., Mueller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M. Juhani, Goyette, Philippe, Pulit, Sara L., Pazoki, Raha, Tanck, MichaelW., Blom, Marieke T., Zhao, XiaoQing, Havulinna, Aki S., Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A., Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J., Franco, Oscar H., Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I., Lemaitre, Rozenn N., Heckbert, Susan R., O'Donnell, Christopher J., Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, Andre G., Hofman, Albert, Stricker, Bruno H. C., de Bakker, Paul I. W., Franks, Paul W., Jansson, Jan-Håkan, Asselbergs, Folkert W., Halushka, Marc K., Maleszewski, Joseph J., Tfelt-Hansen, Jacob, Engstrom, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur A. M., Tan, Hanno L., Bezzina, Connie R., Eijgelsheim, Mark, Rioux, John D., Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M., Siscovick, David S., Arking, Dan E., Sotoodehnia, Nona, Ashar, Foram N., Mitchell, Rebecca N., Albert, Christine M., Newton-Cheh, Christopher, Brody, Jennifer A., Mueller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M. Juhani, Goyette, Philippe, Pulit, Sara L., Pazoki, Raha, Tanck, MichaelW., Blom, Marieke T., Zhao, XiaoQing, Havulinna, Aki S., Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A., Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J., Franco, Oscar H., Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I., Lemaitre, Rozenn N., Heckbert, Susan R., O'Donnell, Christopher J., Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, Andre G., Hofman, Albert, Stricker, Bruno H. C., de Bakker, Paul I. W., Franks, Paul W., Jansson, Jan-Håkan, Asselbergs, Folkert W., Halushka, Marc K., Maleszewski, Joseph J., Tfelt-Hansen, Jacob, Engstrom, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur A. M., Tan, Hanno L., Bezzina, Connie R., Eijgelsheim, Mark, Rioux, John D., Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M., Siscovick, David S., Arking, Dan E., and Sotoodehnia, Nona

Abstract

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Published
2018
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11. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Brain, Onderzoek Precision medicine, Circulatory Health, CMM Groep Kaaij, Team Medisch, Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O'Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno H C, de Bakker, Paul I W, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur A M, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, Sotoodehnia, Nona, Brain, Onderzoek Precision medicine, Circulatory Health, CMM Groep Kaaij, Team Medisch, Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O'Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno H C, de Bakker, Paul I W, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur A M, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, and Sotoodehnia, Nona

Published
2018

12. Erratum : Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I W, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W, Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Subjects
Published Erratum
Abstract

This corrects the article DOI: 10.1038/ncomms15805.

Published
2017

13. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

Author

Haycock, Philip C. Burgess, Stephen Nounu, Aayah Zheng, Jie and Okoli, George N. Bowden, Jack Wade, Kaitlin Hazel and Timpson, Nicholas J. Evans, David M. Willeit, Peter Aviv, Abraham Gaunt, Tomr. Hemani, Gibran Mangino, Massimo and Ellis, Hayley Patricia Kurian, Kathreena M. Pooley, Karen A. and Eeles, Rosalind A. Lee, Jeffrey E. Fang, Shenying Chen, Wei V. Law, Matthew H. Bowdler, Lisa M. Iles, Mark M. Yang, Qiong Worrall, Bradford B. Markus, Hugh Stephen Hung, Rayjean J. Amos, Chris I. Spurdle, Amanda B. Thompson, Deborah J. O'Mara, Tracy A. Wolpin, Brian Amundadottir, Laufey Stolzenberg-Solomon, Rachael Trichopoulou, Antonia and Onland-Moret, Charlotte Lund, Eiliv Duell, Eric J. Canzian, Federico Severi, Gianluca Overvad, Kim Gunter, Marc J. and Tumino, Rosario Svenson, Ulrika van Rij, Andre Baas, Annette F. Bown, Matthew J. Samani, Nilesh J. van t'Hof, Femke N. G. and Tromp, Gerard Jones, Gregory T. Kuivaniemi, Helena and Elmore, James R. Johansson, Mattias Mckay, James Scelo, Ghislaine carreras-Torres, Robert Gaborieau, Valerie and Brennan, Paul Bracci, Paige M. Neale, Rachel E. Olson, Sara H. Gallinger, Steven Li, Donghui Petersen, Gloria M. and Risch, Harvey A. Klein, Alison P. Han, Jiali Abnet, Christian C. Freedman, Neal D. Taylor, Philip R. Maris, John M. Aben, Katja K. Kiemeney, Lambertus A. Vermeulen, Sita H. and Wiencke, John K. Walsh, Kyle M. Wrensch, Margaret Rice, Terri Turnbull, Clare Litchfield, Kevin Paternoster, Lavinia and Standl, Marie Abecasis, Goncalo R. SanGiovanni, John Paul and Li, Yong Mijatovic, Vladan Sapkota, Yadav Low, Siew-Kee and Zondervan, Krina T. Montgomery, Grant W. Nyholt, Dale R. and van Heel, David A. Hunt, Karen Arking, Dan E. Ashar, Foram N. Sotoodehnia, Nona Woo, Daniel Rosand, Jonathan and Comeau, Mary E. Brown, W. Mark Silverman, Edwin K. Hokanson, John E. Cho, Michael H. Hui, Jennie Ferreira, Manuel A. and Thompson, Philip J. Morrison, Alanna C. Felix, Janine F. and Smith, Nicholas L. Christiano, Angela M. Petukhova, Lynn and Betz, Regina C. Fan, Xing Zhang, Xuejun Zhu, Caihong and Langefeld, Carl D. Thompson, Susan D. Wang, Feijie Lin, Xu and Schwartz, David A. Fingerlin, Tasha Rotter, Jerome I. and Cotch, Mary Frances Jensen, Richard A. Munz, Matthias and Dommisch, Henrik Schaefer, Arne S. Han, Fang Ollila, Hanna M. Hillary, Ryan P. Albagha, Omar Ralston, Stuart H. and Zeng, Chenjie Zheng, Wei Shu, Xiao-Ou Reis, Andre Uebe, Steffen Hueffmeier, Ulrike Kawamura, Yoshiya Otowa, Takeshi and Sasaki, Tsukasa Hibberd, Martin Lloyd Davila, Sonia Xie, Gang Siminovitch, Katherine Bei, Jin-Xin Zeng, Yi-Xin and Foersti, Asta Chen, Bowang Landi, Stefano Franke, Andre and Fischer, Annegret Ellinghaus, David Flores, Carlos Noth, Imre Ma, Shwu-Fan Foo, Jia Nee Liu, Jianjun Kim, Jong-Won Cox, David G. Delattre, Olivier Mirabeau, Olivier and Skibola, Christine F. Tang, Clara S. Garcia-Barcelo, Merce and Chang, Kai-Ping Su, Wen-Hui Chang, Yu-Sun Martin, Nicholas G. Gordon, Scott Wade, Tracey D. Lee, Chaeyoung and Kubo, Michiaki Cha, Pei-Chieng Nakamura, Yusuke Levy, Daniel and Kimura, Masayuki Hwang, Shih-Jen Hunt, Steven Spector, Tim Soranzo, Nicole Manichaikul, Aniw. Barr, Graham and Kahali, Bratati Speliotes, Elizabeth Yerges-Armstrong, LauraM. and Cheng, Ching-Yu Jonas, Jost B. Wong, Tien Yin Fogh, Isabella Lin, Kuang Powell, John F. Rice, Kenneth and Relton, Caroline L. Martin, Richard M. Smith, George Davey and Telomeres Mendelian Randomization

Abstract

IMPORTANCE The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

14. Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

Author

Tereshchenko, Larisa G., primary, Sotoodehnia, Nona, additional, Sitlani, Colleen M., additional, Ashar, Foram N., additional, Kabir, Muammar, additional, Biggs, Mary L., additional, Morley, Michael P., additional, Waks, Jonathan W., additional, Soliman, Elsayed Z., additional, Buxton, Alfred E., additional, Biering‐Sørensen, Tor, additional, Solomon, Scott D., additional, Post, Wendy S., additional, Cappola, Thomas P., additional, Siscovick, David S., additional, and Arking, Dan E., additional

Published
2018
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15. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

Author

Haycock, Philip C., Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N., Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J., Evans, David M., Willeit, Peter, Aviv, Abraham, Gaunt, Tomr., Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M., Pooley, Karen A., Eeles, Rosalind A., Lee, Jeffrey E., Fang, Shenying, Chen, Wei V., Law, Matthew H., Bowdler, Lisa M., Iles, Mark M., Yang, Qiong, Worrall, Bradford B., Markus, Hugh Stephen, Hung, Rayjean J., Amos, Chris I., Spurdle, Amanda B., Thompson, Deborah J., O'Mara, Tracy A., Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, Charlotte, Lund, Eiliv, Duell, Eric J., Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J., Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F., Bown, Matthew J., Samani, Nilesh J., van t'Hof, Femke N. G., Tromp, Gerard, Jones, Gregory T., Kuivaniemi, Helena, Elmore, James R., Johansson, Mattias, Mckay, James, Scelo, Ghislaine, carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M., Neale, Rachel E., Olson, Sara H., Gallinger, Steven, Li, Donghui, Petersen, Gloria M., Risch, Harvey A., Klein, Alison P., Han, Jiali, Abnet, Christian C., Freedman, Neal D., Taylor, Philip R., Maris, John M., Aben, Katja K., Kiemeney, Lambertus A., Vermeulen, Sita H., Wiencke, John K., Walsh, Kyle M., Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Goncalo R., SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T., Montgomery, Grant W., Nyholt, Dale R., van Heel, David A., Hunt, Karen, Arking, Dan E., Ashar, Foram N., Sotoodehnia, Nona, Woo, Daniel, Rosand, Jonathan, Comeau, Mary E., Brown, W. Mark, Silverman, Edwin K., Hokanson, John E., Cho, Michael H., Hui, Jennie, Ferreira, Manuel A., Thompson, Philip J., Morrison, Alanna C., Felix, Janine F., Smith, Nicholas L., Christiano, Angela M., Petukhova, Lynn, Betz, Regina C., Fan, Xing, Zhang, Xuejun, Zhu, Caihong, Langefeld, Carl D., Thompson, Susan D., Wang, Feijie, Lin, Xu, Schwartz, David A., Fingerlin, Tasha, Rotter, Jerome I., Cotch, Mary Frances, Jensen, Richard A., Munz, Matthias, Dommisch, Henrik, Schaefer, Arne S., Han, Fang, Ollila, Hanna M., Hillary, Ryan P., Albagha, Omar, Ralston, Stuart H., Zeng, Chenjie, Zheng, Wei, Shu, Xiao-Ou, Reis, Andre, Uebe, Steffen, Hueffmeier, Ulrike, Kawamura, Yoshiya, Otowa, Takeshi, Sasaki, Tsukasa, Hibberd, Martin Lloyd, Davila, Sonia, Xie, Gang, Siminovitch, Katherine, Bei, Jin-Xin, Zeng, Yi-Xin, Foersti, Asta, Chen, Bowang, Landi, Stefano, Franke, Andre, Fischer, Annegret, Ellinghaus, David, Flores, Carlos, Noth, Imre, Ma, Shwu-Fan, Foo, Jia Nee, Liu, Jianjun, Kim, Jong-Won, Cox, David G., Delattre, Olivier, Mirabeau, Olivier, Skibola, Christine F., Tang, Clara S., Garcia-Barcelo, Merce, Chang, Kai-Ping, Su, Wen-Hui, Chang, Yu-Sun, Martin, Nicholas G., Gordon, Scott, Wade, Tracey D., Lee, Chaeyoung, Kubo, Michiaki, Cha, Pei-Chieng, Nakamura, Yusuke, Levy, Daniel, Kimura, Masayuki, Hwang, Shih-Jen, Hunt, Steven, Spector, Tim, Soranzo, Nicole, Manichaikul, Aniw., Barr, Graham, Kahali, Bratati, Speliotes, Elizabeth, Yerges-Armstrong, LauraM., Cheng, Ching-Yu, Jonas, Jost B., Wong, Tien Yin, Fogh, Isabella, Lin, Kuang, Powell, John F., Rice, Kenneth, Relton, Caroline L., Martin, Richard M., Smith, George Davey, Haycock, Philip C., Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N., Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J., Evans, David M., Willeit, Peter, Aviv, Abraham, Gaunt, Tomr., Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M., Pooley, Karen A., Eeles, Rosalind A., Lee, Jeffrey E., Fang, Shenying, Chen, Wei V., Law, Matthew H., Bowdler, Lisa M., Iles, Mark M., Yang, Qiong, Worrall, Bradford B., Markus, Hugh Stephen, Hung, Rayjean J., Amos, Chris I., Spurdle, Amanda B., Thompson, Deborah J., O'Mara, Tracy A., Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, Charlotte, Lund, Eiliv, Duell, Eric J., Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J., Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F., Bown, Matthew J., Samani, Nilesh J., van t'Hof, Femke N. G., Tromp, Gerard, Jones, Gregory T., Kuivaniemi, Helena, Elmore, James R., Johansson, Mattias, Mckay, James, Scelo, Ghislaine, carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M., Neale, Rachel E., Olson, Sara H., Gallinger, Steven, Li, Donghui, Petersen, Gloria M., Risch, Harvey A., Klein, Alison P., Han, Jiali, Abnet, Christian C., Freedman, Neal D., Taylor, Philip R., Maris, John M., Aben, Katja K., Kiemeney, Lambertus A., Vermeulen, Sita H., Wiencke, John K., Walsh, Kyle M., Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Goncalo R., SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T., Montgomery, Grant W., Nyholt, Dale R., van Heel, David A., Hunt, Karen, Arking, Dan E., Ashar, Foram N., Sotoodehnia, Nona, Woo, Daniel, Rosand, Jonathan, Comeau, Mary E., Brown, W. Mark, Silverman, Edwin K., Hokanson, John E., Cho, Michael H., Hui, Jennie, Ferreira, Manuel A., Thompson, Philip J., Morrison, Alanna C., Felix, Janine F., Smith, Nicholas L., Christiano, Angela M., Petukhova, Lynn, Betz, Regina C., Fan, Xing, Zhang, Xuejun, Zhu, Caihong, Langefeld, Carl D., Thompson, Susan D., Wang, Feijie, Lin, Xu, Schwartz, David A., Fingerlin, Tasha, Rotter, Jerome I., Cotch, Mary Frances, Jensen, Richard A., Munz, Matthias, Dommisch, Henrik, Schaefer, Arne S., Han, Fang, Ollila, Hanna M., Hillary, Ryan P., Albagha, Omar, Ralston, Stuart H., Zeng, Chenjie, Zheng, Wei, Shu, Xiao-Ou, Reis, Andre, Uebe, Steffen, Hueffmeier, Ulrike, Kawamura, Yoshiya, Otowa, Takeshi, Sasaki, Tsukasa, Hibberd, Martin Lloyd, Davila, Sonia, Xie, Gang, Siminovitch, Katherine, Bei, Jin-Xin, Zeng, Yi-Xin, Foersti, Asta, Chen, Bowang, Landi, Stefano, Franke, Andre, Fischer, Annegret, Ellinghaus, David, Flores, Carlos, Noth, Imre, Ma, Shwu-Fan, Foo, Jia Nee, Liu, Jianjun, Kim, Jong-Won, Cox, David G., Delattre, Olivier, Mirabeau, Olivier, Skibola, Christine F., Tang, Clara S., Garcia-Barcelo, Merce, Chang, Kai-Ping, Su, Wen-Hui, Chang, Yu-Sun, Martin, Nicholas G., Gordon, Scott, Wade, Tracey D., Lee, Chaeyoung, Kubo, Michiaki, Cha, Pei-Chieng, Nakamura, Yusuke, Levy, Daniel, Kimura, Masayuki, Hwang, Shih-Jen, Hunt, Steven, Spector, Tim, Soranzo, Nicole, Manichaikul, Aniw., Barr, Graham, Kahali, Bratati, Speliotes, Elizabeth, Yerges-Armstrong, LauraM., Cheng, Ching-Yu, Jonas, Jost B., Wong, Tien Yin, Fogh, Isabella, Lin, Kuang, Powell, John F., Rice, Kenneth, Relton, Caroline L., Martin, Richard M., and Smith, George Davey

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer c

Published
2017
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16. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C., Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017

17. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, CMM Groep Kaaij, Infection & Immunity, Aios en Stafsecr. Cardiologie, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I W, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W, Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C., Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, CMM Groep Kaaij, Infection & Immunity, Aios en Stafsecr. Cardiologie, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., de Bakker, Paul I W, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W, Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017

18. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Aios en Stafsecr. Cardiologie, Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, Genetica, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Infection & Immunity, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, de Geus, Eco J. C., Aios en Stafsecr. Cardiologie, Circulatory Health, Onderzoek Precision medicine, Experimentele Afd. Cardiologie 1, Genetica, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Infection & Immunity, Team Medisch, Nolte, Ilja M., Munoz, M. Loretto, Tragante, Vinicius, Amare, Azmeraw T., Jansen, Rick, Vaez, Ahmad, Von Der Heyde, Benedikt, Avery, Christy L., Bis, Joshua C., Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M., Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P., Kumar, Jitender, Van Der Laan, Sander W., Lyytikäinen, Leo-Pekka, Maihofer, Adam X., Minassian, Arpi, van der Most, Peter J., Müller-Nurasyid, Martina, Nivard, Michel G, Salvi, Erika, Stewart, James D., Thayer, Julian F., Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad Hadi, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram N, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G., De Bakker, Paul I.W., Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J., Boomsma, Dorret I., Boucher, Gabrielle, Britton, Annie R., Christophersen, Ingrid E., Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F., Floras, John S., Franco, Oscar H., Friberg, Peter, Gademan, Maaike G.J., Geyer, Mark A., Giedraitis, Vilmantas, Hartman, Catharina A., Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki V., Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M., Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C., Lefrandt, Joop D., Li, Yong, Li, Yun R., Liao, Duanping, Limacher, Marian C., Lin, Henry J, Lindgren, Cecilia M., Lubitz, Steven A., Mahajan, Anubha, McKnight, Barbara, Meyer Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P., Nalls, Mike A., Navis, Gerjan J., Neijts, Melanie, Nikus, Kjell, North, Kari E., O'Connor, Daniel T., Ormel, Johan, Perz, Siegfried, Peters, Annette, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F, Siscovick, David S., Smit, Johannes H, Smith, Nicholas L., Soliman, Elsayed Z, Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., Van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu Ming, Zonderman, Alan B., Cusi, Daniele, Evans, Michele K, Greiser, Karin Halina, van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J, Oldehinkel, Albertine J., Penninx, Brenda Wjh, Reiner, Alexander P, Riese, Harriëtte, Van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G M, Asselbergs, Folkert W., Brundel, Bianca J.J.M., Heckbert, Susan R, Whitsel, Eric A, den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017

19. Association between mitochondrial DNA copy number and sudden cardiac death: findings from the Atherosclerosis Risk in Communities study (ARIC)

Author

Zhang, Yiyi, primary, Guallar, Eliseo, additional, Ashar, Foram N, additional, Longchamps, Ryan J, additional, Castellani, Christina A, additional, Lane, John, additional, Grove, Megan L, additional, Coresh, Josef, additional, Sotoodehnia, Nona, additional, Ilkhanoff, Leonard, additional, Boerwinkle, Eric, additional, Pankratz, Nathan, additional, and Arking, Dan E, additional

Published
2017
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20. Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Author

Tin, Adrienne, primary, Grams, Morgan E., additional, Ashar, Foram N., additional, Lane, John A., additional, Rosenberg, Avi Z., additional, Grove, Megan L., additional, Boerwinkle, Eric, additional, Selvin, Elizabeth, additional, Coresh, Josef, additional, Pankratz, Nathan, additional, and Arking, Dan E., additional

Published
2016
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21. Association between mitochondrial DNA copy number and sudden cardiac death: findings from the Atherosclerosis Risk in Communities study (ARIC).

Author

Yiyi Zhang, Guallar, Eliseo, Ashar, Foram N., Longchamps, Ryan J., Castellani, Christina A., Lane, John, Grove, Megan L., Coresh, Josef, Sotoodehnia, Nona, Ilkhanoff, Leonard, Boerwinkle, Eric, Pankratz, Nathan, and Arking, Dan E.

Abstract

Aims Sudden cardiac death (SCD) is a major public health burden. Mitochondrial dysfunction has been implicated in a wide range of cardiovascular diseases including cardiomyopathy, heart failure, and arrhythmias, but it is unknown if it also contributes to SCD risk. We sought to examine the prospective association between mtDNA copy number (mtDNA-CN), a surrogate marker of mitochondrial function, and SCD risk. Methods and results We measured baseline mtDNA-CN in 11 093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA copy number was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. Sudden cardiac death was defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual without evidence of a non-cardiac cause of cardiac arrest. Sudden cardiac death cases were reviewed and adjudicated by an expert committee. During a median follow-up of 20.4 years, we observed 361 SCD cases. After adjusting for age, race, sex, and centre, the hazard ratio for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% confidence interval 1.58-3.19; P-trend <0.001). When further adjusting for traditional cardiovascular disease risk factors, prevalent coronary heart disease, heart rate, QT interval, and QRS duration, the association remained statistically significant. Spline regression models showed that the association was approximately linear over the range of mtDNA-CN values. No apparent interaction by race or by sex was detected. Conclusion In this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD. [ABSTRACT FROM AUTHOR]

Published
2017
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23. Association of mitochondrial DNA levels with frailty and all-cause mortality

Author

Ashar, Foram N., primary, Moes, Anna, additional, Moore, Ann Z., additional, Grove, Megan L., additional, Chaves, Paulo H. M., additional, Coresh, Josef, additional, Newman, Anne B., additional, Matteini, Amy M., additional, Bandeen-Roche, Karen, additional, Boerwinkle, Eric, additional, Walston, Jeremy D., additional, and Arking, Dan E., additional

Published
2014
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24. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author

Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O'Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno H C, De Bakker, Paul I W, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur A M, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, Sotoodehnia, Nona, and Of The CHARGE Consortium, The SCD Working Group

Subjects
610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

Aims Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

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