Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

Honghuang Lin; Moritz F. Sinner; Jennifer A. Brody; Dan E. Arking; Kathryn L. Lunetta; Michiel Rienstra; Steven A. Lubitz; Jared W. Magnani; Nona Sotoodehnia; Barbara McKnight; David D. McManus; Eric Boerwinkle; Bruce M. Psaty; Jerome I. Rotter; Joshua C. Bis; Richard A. Gibbs; Donna Muzny; Christie L. Kovar; Alanna C. Morrison; Mayetri Gupta; Aaron R. Folsom; Stefan Kääb; Susan R. Heckbert; Alvaro Alonso; Patrick T. Ellinor; Emelia J. Benjamin

doi:10.1016/j.hrthm.2013.11.012

Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

Honghuang Lin, Moritz F. Sinner, Jennifer A. Brody, Dan E. Arking, Kathryn L. Lunetta, Michiel Rienstra, Steven A. Lubitz, Jared W. Magnani, Nona Sotoodehnia, Barbara McKnight, David D. McManus, Eric Boerwinkle, Bruce M. Psaty, Jerome I. Rotter, Joshua C. Bis, Richard A. Gibbs, Donna Muzny, Christie L. Kovar, Alanna C. Morrison, Mayetri GuptaAaron R. Folsom, Stefan Kääb, Susan R. Heckbert, Alvaro Alonso, Patrick T. Ellinor, Emelia J. Benjamin

Epidemiology & Community Health

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

26 Scopus citations

Abstract

Background Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. Objective To study the association of genetic variants with AF at GWAS top loci. Methods In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. Results One common variant (rs11265611; P = 1.70 × 10 ^-6) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r² =.69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P =.01). Conclusions We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

Original language	English (US)
Pages (from-to)	452-457
Number of pages	6
Journal	Heart Rhythm
Volume	11
Issue number	3
DOIs	https://doi.org/10.1016/j.hrthm.2013.11.012
State	Published - Mar 2014

Bibliographical note

Funding Information:
Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Data for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities Study; L. Adrienne Cupples, principal investigator for the Framingham Heart Study; and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts ( HHSN268201100005C , HHSN268201100006C , HHSN268201100007C , HHSN268201100008C , HHSN268201100009C , HHSN2682011000010C , HHSN2682011000011C , and HHSN2682011000012C ). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with the Boston University (contract no. N01-HC-25195 ) and its contract with Affymetrix, Inc, for genome-wide genotyping services (contract no. N02-HL-6-4278) and for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis computing resources at Boston University Medical Campus. This CHS research was supported by NHLBI contracts N01-HC-85239 , N01-HC-85079 , N01-HC-85080 , N01-HC-85081 , N01-HC-85082 , N01-HC-85083 , N01-HC-85084 , N01-HC-85085 , N01-HC-85086 ; N01-HC-35129 , N01 HC-15103 , N01 HC-55222 , N01-HC-75150 , N01-HC-45133 , and HHSN268201200036C as well as by NHLBI grants HL080295 , HL087652 , HL105756 , with additional contribution from NINDS. Additional support was provided through National Institute on Aging of the National Institutes of Public Health grants AG-023629, AG-15928, AG-20098, and AG-027058. See also http://www.chs-nhlbi.org/pi.htm . This project was also supported by NIH grants N01-HC 25195 and 6R01-NS 17950 (to Dr Benjamin); 1RO1HL092577 , 5R21DA027021 , 1RO1HL104156 , 1K24HL105780 , 1R01 HL102214 , and 1RC1HL101056 (to Dr Ellinor); 1RC1HL099452 and American Heart Association grant 09SDG2280087 (to Dr Alonso), and the Netherlands Organisation for Scientific Research grant (Veni grant 016.136.055 ; to Dr Rienstra). This work was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University ( http://www.bumc.bu.edu/evanscenteribr/ ).

Keywords

Arrhythmia
Atrial fibrillation
Epidemiology
Genetics

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10.1016/j.hrthm.2013.11.012

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Lin, H., Sinner, M. F., Brody, J. A., Arking, D. E., Lunetta, K. L., Rienstra, M., Lubitz, S. A., Magnani, J. W., Sotoodehnia, N., McKnight, B., McManus, D. D., Boerwinkle, E., Psaty, B. M., Rotter, J. I., Bis, J. C., Gibbs, R. A., Muzny, D., Kovar, C. L., Morrison, A. C., ... Benjamin, E. J. (2014). Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Heart Rhythm, 11(3), 452-457. https://doi.org/10.1016/j.hrthm.2013.11.012

Lin, H, Sinner, MF, Brody, JA, Arking, DE, Lunetta, KL, Rienstra, M, Lubitz, SA, Magnani, JW, Sotoodehnia, N, McKnight, B, McManus, DD, Boerwinkle, E, Psaty, BM, Rotter, JI, Bis, JC, Gibbs, RA, Muzny, D, Kovar, CL, Morrison, AC, Gupta, M, Folsom, AR, Kääb, S, Heckbert, SR, Alonso, A, Ellinor, PT & Benjamin, EJ 2014, 'Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study', Heart Rhythm, vol. 11, no. 3, pp. 452-457. https://doi.org/10.1016/j.hrthm.2013.11.012

@article{d6f13378e1364120903d5f4257af0473,

title = "Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study",

abstract = "Background Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. Objective To study the association of genetic variants with AF at GWAS top loci. Methods In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. Results One common variant (rs11265611; P = 1.70 × 10 -6) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r2 =.69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P =.01). Conclusions We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.",

keywords = "Arrhythmia, Atrial fibrillation, Epidemiology, Genetics",

author = "Honghuang Lin and Sinner, {Moritz F.} and Brody, {Jennifer A.} and Arking, {Dan E.} and Lunetta, {Kathryn L.} and Michiel Rienstra and Lubitz, {Steven A.} and Magnani, {Jared W.} and Nona Sotoodehnia and Barbara McKnight and McManus, {David D.} and Eric Boerwinkle and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Bis, {Joshua C.} and Gibbs, {Richard A.} and Donna Muzny and Kovar, {Christie L.} and Morrison, {Alanna C.} and Mayetri Gupta and Folsom, {Aaron R.} and Stefan K{\"a}{\"a}b and Heckbert, {Susan R.} and Alvaro Alonso and Ellinor, {Patrick T.} and Benjamin, {Emelia J.}",

note = "Funding Information: Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Data for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities Study; L. Adrienne Cupples, principal investigator for the Framingham Heart Study; and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts ( HHSN268201100005C , HHSN268201100006C , HHSN268201100007C , HHSN268201100008C , HHSN268201100009C , HHSN2682011000010C , HHSN2682011000011C , and HHSN2682011000012C ). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with the Boston University (contract no. N01-HC-25195 ) and its contract with Affymetrix, Inc, for genome-wide genotyping services (contract no. N02-HL-6-4278) and for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis computing resources at Boston University Medical Campus. This CHS research was supported by NHLBI contracts N01-HC-85239 , N01-HC-85079 , N01-HC-85080 , N01-HC-85081 , N01-HC-85082 , N01-HC-85083 , N01-HC-85084 , N01-HC-85085 , N01-HC-85086 ; N01-HC-35129 , N01 HC-15103 , N01 HC-55222 , N01-HC-75150 , N01-HC-45133 , and HHSN268201200036C as well as by NHLBI grants HL080295 , HL087652 , HL105756 , with additional contribution from NINDS. Additional support was provided through National Institute on Aging of the National Institutes of Public Health grants AG-023629, AG-15928, AG-20098, and AG-027058. See also http://www.chs-nhlbi.org/pi.htm . This project was also supported by NIH grants N01-HC 25195 and 6R01-NS 17950 (to Dr Benjamin); 1RO1HL092577 , 5R21DA027021 , 1RO1HL104156 , 1K24HL105780 , 1R01 HL102214 , and 1RC1HL101056 (to Dr Ellinor); 1RC1HL099452 and American Heart Association grant 09SDG2280087 (to Dr Alonso), and the Netherlands Organisation for Scientific Research grant (Veni grant 016.136.055 ; to Dr Rienstra). This work was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University ( http://www.bumc.bu.edu/evanscenteribr/ ). ",

year = "2014",

month = mar,

doi = "10.1016/j.hrthm.2013.11.012",

language = "English (US)",

volume = "11",

pages = "452--457",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier B.V.",

number = "3",

}

TY - JOUR

T1 - Targeted sequencing in candidate genes for atrial fibrillation

T2 - The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

AU - Lin, Honghuang

AU - Sinner, Moritz F.

AU - Brody, Jennifer A.

AU - Arking, Dan E.

AU - Lunetta, Kathryn L.

AU - Rienstra, Michiel

AU - Lubitz, Steven A.

AU - Magnani, Jared W.

AU - Sotoodehnia, Nona

AU - McKnight, Barbara

AU - McManus, David D.

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Bis, Joshua C.

AU - Gibbs, Richard A.

AU - Muzny, Donna

AU - Kovar, Christie L.

AU - Morrison, Alanna C.

AU - Gupta, Mayetri

AU - Folsom, Aaron R.

AU - Kääb, Stefan

AU - Heckbert, Susan R.

AU - Alonso, Alvaro

AU - Ellinor, Patrick T.

AU - Benjamin, Emelia J.

N1 - Funding Information: Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Data for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium” were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities Study; L. Adrienne Cupples, principal investigator for the Framingham Heart Study; and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts ( HHSN268201100005C , HHSN268201100006C , HHSN268201100007C , HHSN268201100008C , HHSN268201100009C , HHSN2682011000010C , HHSN2682011000011C , and HHSN2682011000012C ). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with the Boston University (contract no. N01-HC-25195 ) and its contract with Affymetrix, Inc, for genome-wide genotyping services (contract no. N02-HL-6-4278) and for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis computing resources at Boston University Medical Campus. This CHS research was supported by NHLBI contracts N01-HC-85239 , N01-HC-85079 , N01-HC-85080 , N01-HC-85081 , N01-HC-85082 , N01-HC-85083 , N01-HC-85084 , N01-HC-85085 , N01-HC-85086 ; N01-HC-35129 , N01 HC-15103 , N01 HC-55222 , N01-HC-75150 , N01-HC-45133 , and HHSN268201200036C as well as by NHLBI grants HL080295 , HL087652 , HL105756 , with additional contribution from NINDS. Additional support was provided through National Institute on Aging of the National Institutes of Public Health grants AG-023629, AG-15928, AG-20098, and AG-027058. See also http://www.chs-nhlbi.org/pi.htm . This project was also supported by NIH grants N01-HC 25195 and 6R01-NS 17950 (to Dr Benjamin); 1RO1HL092577 , 5R21DA027021 , 1RO1HL104156 , 1K24HL105780 , 1R01 HL102214 , and 1RC1HL101056 (to Dr Ellinor); 1RC1HL099452 and American Heart Association grant 09SDG2280087 (to Dr Alonso), and the Netherlands Organisation for Scientific Research grant (Veni grant 016.136.055 ; to Dr Rienstra). This work was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University ( http://www.bumc.bu.edu/evanscenteribr/ ).

PY - 2014/3

Y1 - 2014/3

N2 - Background Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. Objective To study the association of genetic variants with AF at GWAS top loci. Methods In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. Results One common variant (rs11265611; P = 1.70 × 10 -6) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r2 =.69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P =.01). Conclusions We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

AB - Background Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. Objective To study the association of genetic variants with AF at GWAS top loci. Methods In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. Results One common variant (rs11265611; P = 1.70 × 10 -6) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r2 =.69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P =.01). Conclusions We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

KW - Arrhythmia

KW - Atrial fibrillation

KW - Epidemiology

KW - Genetics

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U2 - 10.1016/j.hrthm.2013.11.012

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JO - Heart Rhythm

JF - Heart Rhythm

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ER -

Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

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