Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

DE Arking; MJ Junttila; P Goyette; A Huertas-Vazquez; Mark Eijgelsheim; MT Blom; C Newton-Cheh; K Reinier; C Teodorescu; A Uy-Evanado; N Carter-Monroe; KS Kaikkonen; ML Kortelainen; G Boucher; C Lagace; A (Anna) Moes; XQ Zhao; F Kolodgie; Fernando Rivadeneira; Bert Hofman; JCM Witteman; André Uitterlinden; RF Marsman; Raha Pazoki; Abdenasser Bardai; RW Koster; Abbas Dehghan; SJ Hwang; P Bhatnagar; W Post; G Hilton; RJ Prineas; M Li; A Kottgen; G Ehret; E Boerwinkle; J Coresh; WHL Kao; BM Psaty; GF Tomaselli; N Sotoodehnia; DS Siscovick; GL Burke; E Marban; PM Spooner; LA Cupples; J Jui; K Gunson; YA Kesaniemi; AAM Wilde; JC Tardif; CJ O'Donnell; CR Bezzina; R Virmani; Bruno Stricker; HL Tan; CM Albert; A Chakravarti; JD Rioux; HV Huikuri; SS 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

DE Arking, MJ Junttila, P Goyette, A Huertas-Vazquez, Mark Eijgelsheim, MT Blom, C Newton-Cheh, K Reinier, C Teodorescu, A Uy-Evanado, N Carter-Monroe, KS Kaikkonen, ML Kortelainen, G Boucher, C Lagace, A (Anna) Moes, XQ Zhao, F Kolodgie, Fernando Rivadeneira, Bert HofmanJCM Witteman, André Uitterlinden, RF Marsman, Raha Pazoki, Abdenasser Bardai, RW Koster, Abbas Dehghan, SJ Hwang, P Bhatnagar, W Post, G Hilton, RJ Prineas, M Li, A Kottgen, G Ehret, E Boerwinkle, J Coresh, WHL Kao, BM Psaty, GF Tomaselli, N Sotoodehnia, DS Siscovick, GL Burke, E Marban, PM Spooner, LA Cupples, J Jui, K Gunson, YA Kesaniemi, AAM Wilde, JC Tardif, CJ O'Donnell, CR Bezzina, R Virmani, Bruno Stricker, HL Tan, CM Albert, A Chakravarti, JD Rioux, HV Huikuri, SS Chugh

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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 = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 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	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	7
Issue number	6
DOIs	https://doi.org/10.1371/journal.pgen.1002158
Publication status	Published - 2011

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EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-03
EMC NIHES-03-77-02

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Cite this

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., Lagace, C., Moes, A., Zhao, XQ., Kolodgie, F., Rivadeneira, F., ... Chugh, SS. (2011). Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals. PLoS Genetics (print), 7(6). 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 = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 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 = "DE Arking and MJ Junttila and P Goyette and A Huertas-Vazquez and Mark Eijgelsheim and MT Blom and C Newton-Cheh and K Reinier and C Teodorescu and A Uy-Evanado and N Carter-Monroe and KS Kaikkonen and ML Kortelainen and G Boucher and C Lagace and Moes, {A (Anna)} and XQ Zhao and F Kolodgie and Fernando Rivadeneira and Bert Hofman and JCM Witteman and Andr{\'e} Uitterlinden and RF Marsman and Raha Pazoki and Abdenasser Bardai and RW Koster and Abbas Dehghan and SJ Hwang and P Bhatnagar and W Post and G Hilton and RJ Prineas and M Li and A Kottgen and G Ehret and E Boerwinkle and J Coresh and WHL Kao and BM Psaty and GF Tomaselli and N Sotoodehnia and DS Siscovick and GL Burke and E Marban and PM Spooner and LA Cupples and J Jui and K Gunson and YA Kesaniemi and AAM Wilde and JC Tardif and CJ O'Donnell and CR Bezzina and R Virmani and Bruno Stricker and HL Tan and CM Albert and A Chakravarti and JD Rioux and HV Huikuri and SS Chugh",

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

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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, Lagace, C, Moes, A, Zhao, XQ, Kolodgie, F, Rivadeneira, F , Hofman, B, Witteman, JCM, Uitterlinden, A, Marsman, RF, Pazoki, R, Bardai, A, Koster, RW, Dehghan, A, Hwang, SJ, Bhatnagar, P, Post, W, Hilton, G, Prineas, RJ, Li, M, Kottgen, A, Ehret, G, Boerwinkle, E, Coresh, J, Kao, WHL, Psaty, BM, Tomaselli, GF, Sotoodehnia, N, Siscovick, DS, Burke, GL, Marban, E, Spooner, PM, Cupples, LA, Jui, J, Gunson, K, Kesaniemi, YA, Wilde, AAM, Tardif, JC, O'Donnell, CJ, Bezzina, CR, Virmani, R, Stricker, B, 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 (print), vol. 7, no. 6. https://doi.org/10.1371/journal.pgen.1002158

TY - JOUR

T1 - Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

AU - Arking, DE

AU - Junttila, MJ

AU - Goyette, P

AU - Huertas-Vazquez, A

AU - Eijgelsheim, Mark

AU - Blom, MT

AU - Newton-Cheh, C

AU - Reinier, K

AU - Teodorescu, C

AU - Uy-Evanado, A

AU - Carter-Monroe, N

AU - Kaikkonen, KS

AU - Kortelainen, ML

AU - Boucher, G

AU - Lagace, C

AU - Moes, A (Anna)

AU - Zhao, XQ

AU - Kolodgie, F

AU - Rivadeneira, Fernando

AU - Hofman, Bert

AU - Witteman, JCM

AU - Uitterlinden, André

AU - Marsman, RF

AU - Pazoki, Raha

AU - Bardai, Abdenasser

AU - Koster, RW

AU - Dehghan, Abbas

AU - Hwang, SJ

AU - Bhatnagar, P

AU - Post, W

AU - Hilton, G

AU - Prineas, RJ

AU - Li, M

AU - Kottgen, A

AU - Ehret, G

AU - Boerwinkle, E

AU - Coresh, J

AU - Kao, WHL

AU - Psaty, BM

AU - Tomaselli, GF

AU - Sotoodehnia, N

AU - Siscovick, DS

AU - Burke, GL

AU - Marban, E

AU - Spooner, PM

AU - Cupples, LA

AU - Jui, J

AU - Gunson, K

AU - Kesaniemi, YA

AU - Wilde, AAM

AU - Tardif, JC

AU - O'Donnell, CJ

AU - Bezzina, CR

AU - Virmani, R

AU - Stricker, Bruno

AU - Tan, HL

AU - Albert, CM

AU - Chakravarti, A

AU - Rioux, JD

AU - Huikuri, HV

AU - Chugh, SS

PY - 2011

Y1 - 2011

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 = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 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 = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 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).

U2 - 10.1371/journal.pgen.1002158

DO - 10.1371/journal.pgen.1002158

M3 - Article

C2 - 21738491

SN - 1553-7390

VL - 7

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 6

ER -