Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals

Dan E. Arking; M. Juhani Junttila; Philippe Goyette; Adriana Huertas-Vazquez; Mark Eijgelsheim; Marieke T. Blom; Christopher Newton-Cheh; Kyndaron Reinier; Carmen Teodorescu; Audrey Uy-Evanado; Naima Carter-Monroe; Kari S. Kaikkonen; Marja Leena Kortelainen; Gabrielle Boucher; Caroline Lagacé; Anna Moes; Xiao Qing Zhao; Frank Kolodgie; Fernando Rivadeneira; Albert Hofman; Jacqueline C.M. Witteman; André G. Uitterlinden; Roos F. Marsman; Raha Pazoki; Abdennasser Bardai; Rudolph W. Koster; Abbas Dehghan; Shih Jen Hwang; Pallav Bhatnagar; Wendy Post; Gina Hilton; Ronald J. Prineas; Man Li; Anna Köttgen; Georg Ehret; Eric Boerwinkle; Josef Coresh; W. H.Linda Kao; Bruce M. Psaty; Gordon F. Tomaselli; Nona Sotoodehnia; David S. Siscovick; Greg L. Burke; Eduardo Marbán; Peter M. Spooner; L. Adrienne Cupples; Jonathan Jui; Karen Gunson; Y. Antero Kesäniemi; Arthur A.M. Wilde; Jean Claude Tardif; Christopher J. O'Donnell; Connie R. Bezzina; Renu Virmani; Bruno H.C.h. Stricker; Hanno L. Tan; Christine M. Albert; Aravinda Chakravarti; John D. Rioux; Heikki V. Huikuri; Sumeet S. Chugh

doi:10.1371/journal.pgen.1002158

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals

Dan E. Arking, M. Juhani Junttila, Philippe Goyette, Adriana Huertas-Vazquez, Mark Eijgelsheim, Marieke T. Blom, Christopher Newton-Cheh, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, Naima Carter-Monroe, Kari S. Kaikkonen, Marja Leena Kortelainen, Gabrielle Boucher, Caroline Lagacé, Anna Moes, Xiao Qing Zhao, Frank Kolodgie, Fernando Rivadeneira, Albert HofmanJacqueline C.M. Witteman, André G. Uitterlinden, Roos F. Marsman, Raha Pazoki, Abdennasser Bardai, Rudolph W. Koster, Abbas Dehghan, Shih Jen Hwang, Pallav Bhatnagar, Wendy Post, Gina Hilton, Ronald J. Prineas, Man Li, Anna Köttgen, Georg Ehret, Eric Boerwinkle, Josef Coresh, W. H.Linda Kao, Bruce M. Psaty, Gordon F. Tomaselli, Nona Sotoodehnia, David S. Siscovick, Greg L. Burke, Eduardo Marbán, Peter M. Spooner, L. Adrienne Cupples, Jonathan Jui, Karen Gunson, Y. Antero Kesäniemi, Arthur A.M. Wilde, Jean Claude Tardif, Christopher J. O'Donnell, Connie R. Bezzina, Renu Virmani, Bruno H.C.h. Stricker, Hanno L. Tan, Christine M. Albert, Aravinda Chakravarti, John D. Rioux, Heikki V. Huikuri, Sumeet S. Chugh

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10^-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Original language	English (US)
Article number	e1002158
Journal	PLoS genetics
Volume	7
Issue number	6
DOIs	https://doi.org/10.1371/journal.pgen.1002158
State	Published - Jun 2011
Externally published	Yes

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1002158

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Arking, D. E., Junttila, M. J., Goyette, P., Huertas-Vazquez, A., Eijgelsheim, M., Blom, M. T., Newton-Cheh, C., Reinier, K., Teodorescu, C., Uy-Evanado, A., Carter-Monroe, N., Kaikkonen, K. S., Kortelainen, M. L., Boucher, G., Lagacé, C., Moes, A., Zhao, X. Q., Kolodgie, F., Rivadeneira, F., ... Chugh, S. S. (2011). Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals. PLoS genetics, 7(6), Article e1002158. https://doi.org/10.1371/journal.pgen.1002158

Arking, DE, Junttila, MJ, Goyette, P, Huertas-Vazquez, A, Eijgelsheim, M, Blom, MT, Newton-Cheh, C, Reinier, K, Teodorescu, C, Uy-Evanado, A, Carter-Monroe, N, Kaikkonen, KS, Kortelainen, ML, Boucher, G, Lagacé, C, Moes, A, Zhao, XQ, Kolodgie, F, Rivadeneira, F, Hofman, A, Witteman, JCM, Uitterlinden, AG, Marsman, RF, Pazoki, R, Bardai, A, Koster, RW, Dehghan, A, Hwang, SJ, Bhatnagar, P, Post, W, Hilton, G, Prineas, RJ, Li, M, Köttgen, A, Ehret, G, Boerwinkle, E, Coresh, J, Kao, WHL, Psaty, BM, Tomaselli, GF, Sotoodehnia, N, Siscovick, DS, Burke, GL, Marbán, E, Spooner, PM, Cupples, LA, Jui, J, Gunson, K, Kesäniemi, YA, Wilde, AAM, Tardif, JC, O'Donnell, CJ, Bezzina, CR, Virmani, R, Stricker, BHCH, Tan, HL, Albert, CM, Chakravarti, A, Rioux, JD, Huikuri, HV & Chugh, SS 2011, 'Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals', PLoS genetics, vol. 7, no. 6, e1002158. https://doi.org/10.1371/journal.pgen.1002158

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title = "Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals",

abstract = "Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).",

author = "Arking, {Dan E.} and Junttila, {M. Juhani} and Philippe Goyette and Adriana Huertas-Vazquez and Mark Eijgelsheim and Blom, {Marieke T.} and Christopher Newton-Cheh and Kyndaron Reinier and Carmen Teodorescu and Audrey Uy-Evanado and Naima Carter-Monroe and Kaikkonen, {Kari S.} and Kortelainen, {Marja Leena} and Gabrielle Boucher and Caroline Lagac{\'e} and Anna Moes and Zhao, {Xiao Qing} and Frank Kolodgie and Fernando Rivadeneira and Albert Hofman and Witteman, {Jacqueline C.M.} and Uitterlinden, {Andr{\'e} G.} and Marsman, {Roos F.} and Raha Pazoki and Abdennasser Bardai and Koster, {Rudolph W.} and Abbas Dehghan and Hwang, {Shih Jen} and Pallav Bhatnagar and Wendy Post and Gina Hilton and Prineas, {Ronald J.} and Man Li and Anna K{\"o}ttgen and Georg Ehret and Eric Boerwinkle and Josef Coresh and Kao, {W. H.Linda} and Psaty, {Bruce M.} and Tomaselli, {Gordon F.} and Nona Sotoodehnia and Siscovick, {David S.} and Burke, {Greg L.} and Eduardo Marb{\'a}n and Spooner, {Peter M.} and Cupples, {L. Adrienne} and Jonathan Jui and Karen Gunson and Kes{\"a}niemi, {Y. Antero} and Wilde, {Arthur A.M.} and Tardif, {Jean Claude} and O'Donnell, {Christopher J.} and Bezzina, {Connie R.} and Renu Virmani and Stricker, {Bruno H.C.h.} and Tan, {Hanno L.} and Albert, {Christine M.} and Aravinda Chakravarti and Rioux, {John D.} and Huikuri, {Heikki V.} and Chugh, {Sumeet S.}",

year = "2011",

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doi = "10.1371/journal.pgen.1002158",

language = "English (US)",

volume = "7",

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T1 - Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals

AU - Arking, Dan E.

AU - Junttila, M. Juhani

AU - Goyette, Philippe

AU - Huertas-Vazquez, Adriana

AU - Eijgelsheim, Mark

AU - Blom, Marieke T.

AU - Newton-Cheh, Christopher

AU - Reinier, Kyndaron

AU - Teodorescu, Carmen

AU - Uy-Evanado, Audrey

AU - Carter-Monroe, Naima

AU - Kaikkonen, Kari S.

AU - Kortelainen, Marja Leena

AU - Boucher, Gabrielle

AU - Lagacé, Caroline

AU - Moes, Anna

AU - Zhao, Xiao Qing

AU - Kolodgie, Frank

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Witteman, Jacqueline C.M.

AU - Uitterlinden, André G.

AU - Marsman, Roos F.

AU - Pazoki, Raha

AU - Bardai, Abdennasser

AU - Koster, Rudolph W.

AU - Dehghan, Abbas

AU - Hwang, Shih Jen

AU - Bhatnagar, Pallav

AU - Post, Wendy

AU - Hilton, Gina

AU - Prineas, Ronald J.

AU - Li, Man

AU - Köttgen, Anna

AU - Ehret, Georg

AU - Boerwinkle, Eric

AU - Coresh, Josef

AU - Kao, W. H.Linda

AU - Psaty, Bruce M.

AU - Tomaselli, Gordon F.

AU - Sotoodehnia, Nona

AU - Siscovick, David S.

AU - Burke, Greg L.

AU - Marbán, Eduardo

AU - Spooner, Peter M.

AU - Cupples, L. Adrienne

AU - Jui, Jonathan

AU - Gunson, Karen

AU - Kesäniemi, Y. Antero

AU - Wilde, Arthur A.M.

AU - Tardif, Jean Claude

AU - O'Donnell, Christopher J.

AU - Bezzina, Connie R.

AU - Virmani, Renu

AU - Stricker, Bruno H.C.h.

AU - Tan, Hanno L.

AU - Albert, Christine M.

AU - Chakravarti, Aravinda

AU - Rioux, John D.

AU - Huikuri, Heikki V.

AU - Chugh, Sumeet S.

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N2 - Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

AB - Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

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Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals

Abstract

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