Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

Lu-Chen Weng; Kathryn L Lunetta; Martina Müller-Nurasyid; Albert Vernon Smith; Sébastien Thériault; Peter E Weeke; John Barnard; Joshua C Bis; Leo-Pekka Lyytikäinen; Marcus E Kleber; Andreas Martinsson; Henry J Lin; Michiel Rienstra; Stella Trompet; Bouwe P Krijthe; Marcus Dörr; Derek Klarin; Daniel I Chasman; Moritz F Sinner; Melanie Waldenberger; Lenore J Launer; Tamara B Harris; Elsayed Z Soliman; Alvaro Alonso; Guillaume Paré; Pedro L Teixeira; Joshua C Denny; M Benjamin Shoemaker; David R Van Wagoner; Jonathan D Smith; Bruce M Psaty; Nona Sotoodehnia; Kent D Taylor; Mika Kähönen; Kjell Nikus; Graciela E Delgado; Olle Melander; Gunnar Engström; Jie Yao; Xiuqing Guo; Ingrid E Christophersen; Patrick T Ellinor; Bastiaan Geelhoed; Niek Verweij; Peter Macfarlane; Ian Ford; Jan Heeringa; Oscar H Franco; André G Uitterlinden; Uwe Völker; Alexander Teumer; Lynda M Rose; Stefan Kääb; Vilmundur Gudnason; Dan E Arking; David Conen; Dan M Roden; Mina K Chung; Susan R Heckbert; Emelia J Benjamin; Terho Lehtimäki; Winfried März; J Gustav Smith; Jerome I Rotter; Pim van der Harst; J Wouter Jukema; Bruno H Stricker; Stephan B Felix; Christine M Albert; Steven A Lubitz

doi:10.1038/s41598-017-09396-7

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

Lu-Chen Weng, Kathryn L Lunetta, Martina Müller-Nurasyid, Albert Vernon Smith, Sébastien Thériault, Peter E Weeke, John Barnard, Joshua C Bis, Leo-Pekka Lyytikäinen, Marcus E Kleber, Andreas Martinsson, Henry J Lin, Michiel Rienstra, Stella Trompet, Bouwe P Krijthe, Marcus Dörr, Derek Klarin, Daniel I Chasman, Moritz F Sinner, Melanie WaldenbergerLenore J Launer, Tamara B Harris, Elsayed Z Soliman, Alvaro Alonso, Guillaume Paré, Pedro L Teixeira, Joshua C Denny, M Benjamin Shoemaker, David R Van Wagoner, Jonathan D Smith, Bruce M Psaty, Nona Sotoodehnia, Kent D Taylor, Mika Kähönen, Kjell Nikus, Graciela E Delgado, Olle Melander, Gunnar Engström, Jie Yao, Xiuqing Guo, Ingrid E Christophersen, Patrick T Ellinor, Bastiaan Geelhoed, Niek Verweij, Peter Macfarlane, Ian Ford, Jan Heeringa, Oscar H Franco, André G Uitterlinden, Uwe Völker, Alexander Teumer, Lynda M Rose, Stefan Kääb, Vilmundur Gudnason, Dan E Arking, David Conen, Dan M Roden, Mina K Chung, Susan R Heckbert, Emelia J Benjamin, Terho Lehtimäki, Winfried März, J Gustav Smith, Jerome I Rotter, Pim van der Harst, J Wouter Jukema, Bruno H Stricker, Stephan B Felix, Christine M Albert, Steven A Lubitz

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

Abstract

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Original language	English
Article number	11303
Pages (from-to)	11303
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-09396-7
Publication status	Published - 1 Dec 2017
Externally published	Yes

Keywords

Age Factors
Aged
Atrial Fibrillation/genetics
Body Mass Index
Chromosomes, Human, Pair 4/genetics
Epistasis, Genetic
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Hypertension/genetics
Male
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide/genetics
Reproducibility of Results
Risk Factors
Sex Characteristics

Access to Document

10.1038/s41598-017-09396-7

Cite this

Weng, L.-C., Lunetta, K. L., Müller-Nurasyid, M., Smith, A. V., Thériault, S., Weeke, P. E., Barnard, J., Bis, J. C., Lyytikäinen, L.-P., Kleber, M. E., Martinsson, A., Lin, H. J., Rienstra, M., Trompet, S., Krijthe, B. P., Dörr, M., Klarin, D., Chasman, D. I., Sinner, M. F., ... Lubitz, S. A. (2017). Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. Scientific Reports, 7(1), 11303. Article 11303. https://doi.org/10.1038/s41598-017-09396-7

@article{5983ca5e1f1e4efa8091b594e1c0dec1,

title = "Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium",

abstract = "It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.",

keywords = "Age Factors, Aged, Atrial Fibrillation/genetics, Body Mass Index, Chromosomes, Human, Pair 4/genetics, Epistasis, Genetic, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension/genetics, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide/genetics, Reproducibility of Results, Risk Factors, Sex Characteristics",

author = "Lu-Chen Weng and Lunetta, {Kathryn L} and Martina M{\"u}ller-Nurasyid and Smith, {Albert Vernon} and S{\'e}bastien Th{\'e}riault and Weeke, {Peter E} and John Barnard and Bis, {Joshua C} and Leo-Pekka Lyytik{\"a}inen and Kleber, {Marcus E} and Andreas Martinsson and Lin, {Henry J} and Michiel Rienstra and Stella Trompet and Krijthe, {Bouwe P} and Marcus D{\"o}rr and Derek Klarin and Chasman, {Daniel I} and Sinner, {Moritz F} and Melanie Waldenberger and Launer, {Lenore J} and Harris, {Tamara B} and Soliman, {Elsayed Z} and Alvaro Alonso and Guillaume Par{\'e} and Teixeira, {Pedro L} and Denny, {Joshua C} and Shoemaker, {M Benjamin} and {Van Wagoner}, {David R} and Smith, {Jonathan D} and Psaty, {Bruce M} and Nona Sotoodehnia and Taylor, {Kent D} and Mika K{\"a}h{\"o}nen and Kjell Nikus and Delgado, {Graciela E} and Olle Melander and Gunnar Engstr{\"o}m and Jie Yao and Xiuqing Guo and Christophersen, {Ingrid E} and Ellinor, {Patrick T} and Bastiaan Geelhoed and Niek Verweij and Peter Macfarlane and Ian Ford and Jan Heeringa and Franco, {Oscar H} and Uitterlinden, {Andr{\'e} G} and Uwe V{\"o}lker and Alexander Teumer and Rose, {Lynda M} and Stefan K{\"a}{\"a}b and Vilmundur Gudnason and Arking, {Dan E} and David Conen and Roden, {Dan M} and Chung, {Mina K} and Heckbert, {Susan R} and Benjamin, {Emelia J} and Terho Lehtim{\"a}ki and Winfried M{\"a}rz and Smith, {J Gustav} and Rotter, {Jerome I} and {van der Harst}, Pim and Jukema, {J Wouter} and Stricker, {Bruno H} and Felix, {Stephan B} and Albert, {Christine M} and Lubitz, {Steven A}",

note = "Funding Information: The authors would like to thank all subjects, staffs, and investigators of participating studies. AFNET/KORA: This work is funded by the European Commision{\textquoteright}s Horizon 2020 research and innovation programme (grant number 633196: CATCH ME to Dr. Sinner). AGES: The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This work was additionally supported by American Heart Association grant 16EIA26410001 (Alonso). BioVU: The dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/ NIGMS. CCAF: R01 HL090620 and R01 HL111314 from the National Heart, Lung, and Blood Institute (Chung, Barnard, J. Smith, Van Wagoner); NIH/NCRR, CTSA 1UL-RR024989 (Chung, Van Wagoner); Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic (Chung); Tomsich Atrial Fibrillation Research Fund (Chung); Leducq Foundation 07-CVD 03 (Van Wagoner, Chung); Atrial Fibrillation Innovation Center, State of Ohio (Van Wagoner, Chung). CHS: This Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Psaty serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. FINCAVAS: The Finnish Cardiovascular Study (FINCAVAS) has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. FHS: Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the FHS through 1R01HL128914; 2R01 HL092577; HHSN268201500001I; N01-HC 25195; and Framingham Atrial Fibrillation/Flutter reviewed through 2012 dataset was provided by NHLBI grants 1R01HL092577, 1R01HL102214, 1RC1HL101056 and NINDS grant 6R01-NS-17950. LURIC: The Ludwigshafen Risk and Cardiovascular Health study was supported by the seventh framework program of the European commission (RiskyCAD, grant agreement number 305739). Support for genotyping was provided by the seventh framework program of the European commission (AtheroRemo, grant agreement number 201668). MESA: The Multi-Ethnic Study of Atherosclerosis study was supported by NIH contracts HHSN2682015000031, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and by grants UL1-TR-000040, UL1-TR-001079, and UL1-RR-025005 from NCRR. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. PREVEND: The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by grants from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). RS: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics, Inc., and AXA. Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics, Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network {\textquoteleft}Greifswald Approach to Individualized Medicine (GANI_MED){\textquoteright} funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Cach{\'e} Campus program of the InterSystems GmbH. Funding Information: Competing Interests: This work was supported by grants from the NIH K23HL114724 (Lubitz), 1RO1HL092577 and R01HL128914 (Benjamin and Ellinor), K24HL105780 (Ellinor), Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 (Lubitz), an Established Investigator Award from the American Heart Association 13EIA14220013 (Ellinor), the Fondation Leducq 14CVD01 (Ellinor). Dr. Ellinor is the principal investigator on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. Dr. Christophersen is supported by a mobility grant from the Research Council of Norway [240149/F20]. Dr. Klarin is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number T32 HL007734. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41598-017-09396-7",

language = "English",

volume = "7",

pages = "11303",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Weng, L-C, Lunetta, KL, Müller-Nurasyid, M, Smith, AV, Thériault, S, Weeke, PE, Barnard, J, Bis, JC, Lyytikäinen, L-P, Kleber, ME, Martinsson, A, Lin, HJ, Rienstra, M, Trompet, S, Krijthe, BP, Dörr, M, Klarin, D, Chasman, DI, Sinner, MF, Waldenberger, M, Launer, LJ, Harris, TB, Soliman, EZ, Alonso, A, Paré, G, Teixeira, PL, Denny, JC, Shoemaker, MB, Van Wagoner, DR, Smith, JD, Psaty, BM, Sotoodehnia, N, Taylor, KD, Kähönen, M, Nikus, K, Delgado, GE, Melander, O, Engström, G, Yao, J, Guo, X, Christophersen, IE, Ellinor, PT, Geelhoed, B, Verweij, N, Macfarlane, P, Ford, I, Heeringa, J, Franco, OH, Uitterlinden, AG, Völker, U, Teumer, A, Rose, LM, Kääb, S, Gudnason, V, Arking, DE, Conen, D, Roden, DM, Chung, MK, Heckbert, SR, Benjamin, EJ, Lehtimäki, T, März, W, Smith, JG, Rotter, JI, van der Harst, P, Jukema, JW, Stricker, BH, Felix, SB, Albert, CM & Lubitz, SA 2017, 'Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium', Scientific Reports, vol. 7, no. 1, 11303, pp. 11303. https://doi.org/10.1038/s41598-017-09396-7

TY - JOUR

T1 - Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation

T2 - The AFGen Consortium

AU - Weng, Lu-Chen

AU - Lunetta, Kathryn L

AU - Müller-Nurasyid, Martina

AU - Smith, Albert Vernon

AU - Thériault, Sébastien

AU - Weeke, Peter E

AU - Barnard, John

AU - Bis, Joshua C

AU - Lyytikäinen, Leo-Pekka

AU - Kleber, Marcus E

AU - Martinsson, Andreas

AU - Lin, Henry J

AU - Rienstra, Michiel

AU - Trompet, Stella

AU - Krijthe, Bouwe P

AU - Dörr, Marcus

AU - Klarin, Derek

AU - Chasman, Daniel I

AU - Sinner, Moritz F

AU - Waldenberger, Melanie

AU - Launer, Lenore J

AU - Harris, Tamara B

AU - Soliman, Elsayed Z

AU - Alonso, Alvaro

AU - Paré, Guillaume

AU - Teixeira, Pedro L

AU - Denny, Joshua C

AU - Shoemaker, M Benjamin

AU - Van Wagoner, David R

AU - Smith, Jonathan D

AU - Psaty, Bruce M

AU - Sotoodehnia, Nona

AU - Taylor, Kent D

AU - Kähönen, Mika

AU - Nikus, Kjell

AU - Delgado, Graciela E

AU - Melander, Olle

AU - Engström, Gunnar

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Christophersen, Ingrid E

AU - Ellinor, Patrick T

AU - Geelhoed, Bastiaan

AU - Verweij, Niek

AU - Macfarlane, Peter

AU - Ford, Ian

AU - Heeringa, Jan

AU - Franco, Oscar H

AU - Uitterlinden, André G

AU - Völker, Uwe

AU - Teumer, Alexander

AU - Rose, Lynda M

AU - Kääb, Stefan

AU - Gudnason, Vilmundur

AU - Arking, Dan E

AU - Conen, David

AU - Roden, Dan M

AU - Chung, Mina K

AU - Heckbert, Susan R

AU - Benjamin, Emelia J

AU - Lehtimäki, Terho

AU - März, Winfried

AU - Smith, J Gustav

AU - Rotter, Jerome I

AU - van der Harst, Pim

AU - Jukema, J Wouter

AU - Stricker, Bruno H

AU - Felix, Stephan B

AU - Albert, Christine M

AU - Lubitz, Steven A

N1 - Funding Information: The authors would like to thank all subjects, staffs, and investigators of participating studies. AFNET/KORA: This work is funded by the European Commision’s Horizon 2020 research and innovation programme (grant number 633196: CATCH ME to Dr. Sinner). AGES: The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This work was additionally supported by American Heart Association grant 16EIA26410001 (Alonso). BioVU: The dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/ NIGMS. CCAF: R01 HL090620 and R01 HL111314 from the National Heart, Lung, and Blood Institute (Chung, Barnard, J. Smith, Van Wagoner); NIH/NCRR, CTSA 1UL-RR024989 (Chung, Van Wagoner); Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic (Chung); Tomsich Atrial Fibrillation Research Fund (Chung); Leducq Foundation 07-CVD 03 (Van Wagoner, Chung); Atrial Fibrillation Innovation Center, State of Ohio (Van Wagoner, Chung). CHS: This Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Psaty serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. FINCAVAS: The Finnish Cardiovascular Study (FINCAVAS) has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. FHS: Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the FHS through 1R01HL128914; 2R01 HL092577; HHSN268201500001I; N01-HC 25195; and Framingham Atrial Fibrillation/Flutter reviewed through 2012 dataset was provided by NHLBI grants 1R01HL092577, 1R01HL102214, 1RC1HL101056 and NINDS grant 6R01-NS-17950. LURIC: The Ludwigshafen Risk and Cardiovascular Health study was supported by the seventh framework program of the European commission (RiskyCAD, grant agreement number 305739). Support for genotyping was provided by the seventh framework program of the European commission (AtheroRemo, grant agreement number 201668). MESA: The Multi-Ethnic Study of Atherosclerosis study was supported by NIH contracts HHSN2682015000031, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and by grants UL1-TR-000040, UL1-TR-001079, and UL1-RR-025005 from NCRR. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. PREVEND: The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by grants from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). RS: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics, Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics, Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Funding Information: Competing Interests: This work was supported by grants from the NIH K23HL114724 (Lubitz), 1RO1HL092577 and R01HL128914 (Benjamin and Ellinor), K24HL105780 (Ellinor), Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 (Lubitz), an Established Investigator Award from the American Heart Association 13EIA14220013 (Ellinor), the Fondation Leducq 14CVD01 (Ellinor). Dr. Ellinor is the principal investigator on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. Dr. Christophersen is supported by a mobility grant from the Research Council of Norway [240149/F20]. Dr. Klarin is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number T32 HL007734. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

AB - It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

KW - Age Factors

KW - Aged

KW - Atrial Fibrillation/genetics

KW - Body Mass Index

KW - Chromosomes, Human, Pair 4/genetics

KW - Epistasis, Genetic

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Hypertension/genetics

KW - Male

KW - Middle Aged

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide/genetics

KW - Reproducibility of Results

KW - Risk Factors

KW - Sex Characteristics

UR - http://www.scopus.com/inward/record.url?scp=85029282039&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-09396-7

DO - 10.1038/s41598-017-09396-7

M3 - Article

C2 - 28900195

SN - 2045-2322

VL - 7

SP - 11303

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11303

ER -

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this