A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Foram N Ashar; Rebecca N Mitchell; Christine M Albert; Christopher Newton-Cheh; Jennifer A Brody; Martina Müller-Nurasyid; Anna Moes; Thomas Meitinger; Angel Mak; Heikki Huikuri; M Juhani Junttila; Philippe Goyette; Sara L Pulit; Raha Pazoki; Michael W Tanck; Marieke T Blom; XiaoQing Zhao; Aki S Havulinna; Reza Jabbari; Charlotte Glinge; Vinicius Tragante; Stefan A Escher; Aravinda Chakravarti; Georg Ehret; Josef Coresh; Man Li; Ronald J Prineas; Oscar H Franco; Pui-Yan Kwok; Thomas Lumley; Florence Dumas; Barbara McKnight; Jerome I Rotter; Rozenn N Lemaitre; Susan R Heckbert; Christopher J O'Donnell; Shih-Jen Hwang; Jean-Claude Tardif; Martin VanDenburgh; André G Uitterlinden; Albert Hofman; Bruno H C Stricker; Paul I W de Bakker; Paul W Franks; Jan-Hakan Jansson; Folkert W Asselbergs; Marc K Halushka; Jacob Tfelt-Hansen; Thomas Engstrøm; Nona Sotoodehnia; SCD working group of the CHARGE Consortium

doi:10.1093/eurheartj/ehy474

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Foram N Ashar, Rebecca N Mitchell, Christine M Albert, Christopher Newton-Cheh, Jennifer A Brody, Martina Müller-Nurasyid, Anna Moes, Thomas Meitinger, Angel Mak, Heikki Huikuri, M Juhani Junttila, Philippe Goyette, Sara L Pulit, Raha Pazoki, Michael W Tanck, Marieke T Blom, XiaoQing Zhao, Aki S Havulinna, Reza Jabbari, Charlotte GlingeVinicius Tragante, Stefan A Escher, Aravinda Chakravarti, Georg Ehret, Josef Coresh, Man Li, Ronald J Prineas, Oscar H Franco, Pui-Yan Kwok, Thomas Lumley, Florence Dumas, Barbara McKnight, Jerome I Rotter, Rozenn N Lemaitre, Susan R Heckbert, Christopher J O'Donnell, Shih-Jen Hwang, Jean-Claude Tardif, Martin VanDenburgh, André G Uitterlinden, Albert Hofman, Bruno H C Stricker, Paul I W de Bakker, Paul W Franks, Jan-Hakan Jansson, Folkert W Asselbergs, Marc K Halushka, Jacob Tfelt-Hansen, Thomas Engstrøm, Nona Sotoodehnia, SCD working group of the CHARGE Consortium

28 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	European Heart Journal
Vol/bind	39
Udgave nummer	44
Sider (fra-til)	3961-3969
ISSN	0195-668X
DOI	https://doi.org/10.1093/eurheartj/ehy474
Status	Udgivet - 21 nov. 2018

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1093/eurheartj/ehy474

ehy474.pdfForlagets udgivne version, 501 KB

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247663/Licens: Andet

Citationsformater

Ashar, F. N., Mitchell, R. N., Albert, C. M., Newton-Cheh, C., Brody, J. A., Müller-Nurasyid, M., Moes, A., Meitinger, T., Mak, A., Huikuri, H., Junttila, M. J., Goyette, P., Pulit, S. L., Pazoki, R., Tanck, M. W., Blom, M. T., Zhao, X., Havulinna, A. S., Jabbari, R., ... SCD working group of the CHARGE Consortium (2018). A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. European Heart Journal, 39(44), 3961-3969. https://doi.org/10.1093/eurheartj/ehy474

Ashar, FN, Mitchell, RN, Albert, CM, Newton-Cheh, C, Brody, JA, Müller-Nurasyid, M, Moes, A, Meitinger, T, Mak, A, Huikuri, H, Junttila, MJ, Goyette, P, Pulit, SL, Pazoki, R, Tanck, MW, Blom, MT, Zhao, X, Havulinna, AS, Jabbari, R, Glinge, C, Tragante, V, Escher, SA, Chakravarti, A, Ehret, G, Coresh, J, Li, M, Prineas, RJ, Franco, OH, Kwok, P-Y, Lumley, T, Dumas, F, McKnight, B, Rotter, JI, Lemaitre, RN, Heckbert, SR, O'Donnell, CJ, Hwang, S-J, Tardif, J-C, VanDenburgh, M, Uitterlinden, AG, Hofman, A, Stricker, BHC, de Bakker, PIW, Franks, PW, Jansson, J-H, Asselbergs, FW, Halushka, MK, Tfelt-Hansen, J , Engstrøm, T, Sotoodehnia, N & SCD working group of the CHARGE Consortium 2018, 'A comprehensive evaluation of the genetic architecture of sudden cardiac arrest', European Heart Journal, bind 39, nr. 44, s. 3961-3969. https://doi.org/10.1093/eurheartj/ehy474

@article{f03ee9faeec24be0bbc95cd58ece6ca8,

title = "A comprehensive evaluation of the genetic architecture of sudden cardiac arrest",

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.",

keywords = "Genome-wide association study, Mendelian randomization, Sudden cardiac arrest",

author = "Ashar, {Foram N} and Mitchell, {Rebecca N} and Albert, {Christine M} and Christopher Newton-Cheh and Brody, {Jennifer A} and Martina M{\"u}ller-Nurasyid and Anna Moes and Thomas Meitinger and Angel Mak and Heikki Huikuri and Junttila, {M Juhani} and Philippe Goyette and Pulit, {Sara L} and Raha Pazoki and Tanck, {Michael W} and Blom, {Marieke T} and XiaoQing Zhao and Havulinna, {Aki S} and Reza Jabbari and Charlotte Glinge and Vinicius Tragante and Escher, {Stefan A} and Aravinda Chakravarti and Georg Ehret and Josef Coresh and Man Li and Prineas, {Ronald J} and Franco, {Oscar H} and Pui-Yan Kwok and Thomas Lumley and Florence Dumas and Barbara McKnight and Rotter, {Jerome I} and Lemaitre, {Rozenn N} and Heckbert, {Susan R} and O'Donnell, {Christopher J} and Shih-Jen Hwang and Jean-Claude Tardif and Martin VanDenburgh and Uitterlinden, {Andr{\'e} G} and Albert Hofman and Stricker, {Bruno H C} and {de Bakker}, {Paul I W} and Franks, {Paul W} and Jan-Hakan Jansson and Asselbergs, {Folkert W} and Halushka, {Marc K} and Jacob Tfelt-Hansen and Thomas Engstr{\o}m and Nona Sotoodehnia and {SCD working group of the CHARGE Consortium}",

year = "2018",

month = nov,

day = "21",

doi = "10.1093/eurheartj/ehy474",

language = "English",

volume = "39",

pages = "3961--3969",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "44",

}

TY - JOUR

T1 - A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

AU - Ashar, Foram N

AU - Mitchell, Rebecca N

AU - Albert, Christine M

AU - Newton-Cheh, Christopher

AU - Brody, Jennifer A

AU - Müller-Nurasyid, Martina

AU - Moes, Anna

AU - Meitinger, Thomas

AU - Mak, Angel

AU - Huikuri, Heikki

AU - Junttila, M Juhani

AU - Goyette, Philippe

AU - Pulit, Sara L

AU - Pazoki, Raha

AU - Tanck, Michael W

AU - Blom, Marieke T

AU - Zhao, XiaoQing

AU - Havulinna, Aki S

AU - Jabbari, Reza

AU - Glinge, Charlotte

AU - Tragante, Vinicius

AU - Escher, Stefan A

AU - Chakravarti, Aravinda

AU - Ehret, Georg

AU - Coresh, Josef

AU - Li, Man

AU - Prineas, Ronald J

AU - Franco, Oscar H

AU - Kwok, Pui-Yan

AU - Lumley, Thomas

AU - Dumas, Florence

AU - McKnight, Barbara

AU - Rotter, Jerome I

AU - Lemaitre, Rozenn N

AU - Heckbert, Susan R

AU - O'Donnell, Christopher J

AU - Hwang, Shih-Jen

AU - Tardif, Jean-Claude

AU - VanDenburgh, Martin

AU - Uitterlinden, André G

AU - Hofman, Albert

AU - Stricker, Bruno H C

AU - de Bakker, Paul I W

AU - Franks, Paul W

AU - Jansson, Jan-Hakan

AU - Asselbergs, Folkert W

AU - Halushka, Marc K

AU - Tfelt-Hansen, Jacob

AU - Engstrøm, Thomas

AU - Sotoodehnia, Nona

AU - SCD working group of the CHARGE Consortium

PY - 2018/11/21

Y1 - 2018/11/21

N2 - 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.

AB - 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.

KW - Genome-wide association study

KW - Mendelian randomization

KW - Sudden cardiac arrest

U2 - 10.1093/eurheartj/ehy474

DO - 10.1093/eurheartj/ehy474

M3 - Journal article

C2 - 30169657

SN - 0195-668X

VL - 39

SP - 3961

EP - 3969

JO - European Heart Journal

JF - European Heart Journal

IS - 44

ER -

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater