Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development

Jonas B. Nielsen, Lars G. Fritsche, Wei Zhou, Tanya M. Teslovich, Oddgeir L. Holmen, Stefan Gustafsson, Maiken E. Gabrielsen, Ellen M. Schmidt, Robin Beaumont, Brooke N. Wolford, Maoxuan Lin, Chad M. Brummett, Michael H. Preuss, Lena Refsgaard, Erwin P. Bottinger, Sarah E. Graham, Ida Surakka, Yunhan Chu, Anne Heidi Skogholt, Håvard DalenAlan P. Boyle, Hakan Oral, Todd J. Herron, Jacob Kitzman, José Jalife, Jesper H. Svendsen, Morten S. Olesen, Inger Njølstad, Maja Lisa Løchen, Aris Baras, Omri Gottesman, Anthony Marcketta, Colm O'Dushlaine, Marylyn D. Ritchie, Tom Wilsgaard, Ruth J.F. Loos, Timothy M. Frayling, Michael Boehnke, Erik Ingelsson, David J. Carey, Frederick E. Dewey, Hyun M. Kang, Gonçalo R. Abecasis, Kristian Hveem, Cristen J. Willer

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

Original languageEnglish (US)
Pages (from-to)103-115
Number of pages13
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2018

Fingerprint

Atrial Fibrillation
Genome
Nucleotides
Connectin
Fetal Heart
Premature Mortality
Chromosome Mapping
Chromosomes, Human, Pair 1
Genome-Wide Association Study
Elasticity
Norway
Fetal Development
Muscle Cells
Cardiac Arrhythmias
Cell Differentiation
Myocardium
Skeletal Muscle
Heart Failure
Stroke
Muscles

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Nielsen, Jonas B. ; Fritsche, Lars G. ; Zhou, Wei ; Teslovich, Tanya M. ; Holmen, Oddgeir L. ; Gustafsson, Stefan ; Gabrielsen, Maiken E. ; Schmidt, Ellen M. ; Beaumont, Robin ; Wolford, Brooke N. ; Lin, Maoxuan ; Brummett, Chad M. ; Preuss, Michael H. ; Refsgaard, Lena ; Bottinger, Erwin P. ; Graham, Sarah E. ; Surakka, Ida ; Chu, Yunhan ; Skogholt, Anne Heidi ; Dalen, Håvard ; Boyle, Alan P. ; Oral, Hakan ; Herron, Todd J. ; Kitzman, Jacob ; Jalife, José ; Svendsen, Jesper H. ; Olesen, Morten S. ; Njølstad, Inger ; Løchen, Maja Lisa ; Baras, Aris ; Gottesman, Omri ; Marcketta, Anthony ; O'Dushlaine, Colm ; Ritchie, Marylyn D. ; Wilsgaard, Tom ; Loos, Ruth J.F. ; Frayling, Timothy M. ; Boehnke, Michael ; Ingelsson, Erik ; Carey, David J. ; Dewey, Frederick E. ; Kang, Hyun M. ; Abecasis, Gonçalo R. ; Hveem, Kristian ; Willer, Cristen J. / Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 1. pp. 103-115.
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abstract = "Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.",
author = "Nielsen, {Jonas B.} and Fritsche, {Lars G.} and Wei Zhou and Teslovich, {Tanya M.} and Holmen, {Oddgeir L.} and Stefan Gustafsson and Gabrielsen, {Maiken E.} and Schmidt, {Ellen M.} and Robin Beaumont and Wolford, {Brooke N.} and Maoxuan Lin and Brummett, {Chad M.} and Preuss, {Michael H.} and Lena Refsgaard and Bottinger, {Erwin P.} and Graham, {Sarah E.} and Ida Surakka and Yunhan Chu and Skogholt, {Anne Heidi} and H{\aa}vard Dalen and Boyle, {Alan P.} and Hakan Oral and Herron, {Todd J.} and Jacob Kitzman and Jos{\'e} Jalife and Svendsen, {Jesper H.} and Olesen, {Morten S.} and Inger Nj{\o}lstad and L{\o}chen, {Maja Lisa} and Aris Baras and Omri Gottesman and Anthony Marcketta and Colm O'Dushlaine and Ritchie, {Marylyn D.} and Tom Wilsgaard and Loos, {Ruth J.F.} and Frayling, {Timothy M.} and Michael Boehnke and Erik Ingelsson and Carey, {David J.} and Dewey, {Frederick E.} and Kang, {Hyun M.} and Abecasis, {Gon{\cc}alo R.} and Kristian Hveem and Willer, {Cristen J.}",
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Nielsen, JB, Fritsche, LG, Zhou, W, Teslovich, TM, Holmen, OL, Gustafsson, S, Gabrielsen, ME, Schmidt, EM, Beaumont, R, Wolford, BN, Lin, M, Brummett, CM, Preuss, MH, Refsgaard, L, Bottinger, EP, Graham, SE, Surakka, I, Chu, Y, Skogholt, AH, Dalen, H, Boyle, AP, Oral, H, Herron, TJ, Kitzman, J, Jalife, J, Svendsen, JH, Olesen, MS, Njølstad, I, Løchen, ML, Baras, A, Gottesman, O, Marcketta, A, O'Dushlaine, C, Ritchie, MD, Wilsgaard, T, Loos, RJF, Frayling, TM, Boehnke, M, Ingelsson, E, Carey, DJ, Dewey, FE, Kang, HM, Abecasis, GR, Hveem, K & Willer, CJ 2018, 'Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development', American Journal of Human Genetics, vol. 102, no. 1, pp. 103-115. https://doi.org/10.1016/j.ajhg.2017.12.003

Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development. / Nielsen, Jonas B.; Fritsche, Lars G.; Zhou, Wei; Teslovich, Tanya M.; Holmen, Oddgeir L.; Gustafsson, Stefan; Gabrielsen, Maiken E.; Schmidt, Ellen M.; Beaumont, Robin; Wolford, Brooke N.; Lin, Maoxuan; Brummett, Chad M.; Preuss, Michael H.; Refsgaard, Lena; Bottinger, Erwin P.; Graham, Sarah E.; Surakka, Ida; Chu, Yunhan; Skogholt, Anne Heidi; Dalen, Håvard; Boyle, Alan P.; Oral, Hakan; Herron, Todd J.; Kitzman, Jacob; Jalife, José; Svendsen, Jesper H.; Olesen, Morten S.; Njølstad, Inger; Løchen, Maja Lisa; Baras, Aris; Gottesman, Omri; Marcketta, Anthony; O'Dushlaine, Colm; Ritchie, Marylyn D.; Wilsgaard, Tom; Loos, Ruth J.F.; Frayling, Timothy M.; Boehnke, Michael; Ingelsson, Erik; Carey, David J.; Dewey, Frederick E.; Kang, Hyun M.; Abecasis, Gonçalo R.; Hveem, Kristian; Willer, Cristen J.

In: American Journal of Human Genetics, Vol. 102, No. 1, 04.01.2018, p. 103-115.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development

AU - Nielsen, Jonas B.

AU - Fritsche, Lars G.

AU - Zhou, Wei

AU - Teslovich, Tanya M.

AU - Holmen, Oddgeir L.

AU - Gustafsson, Stefan

AU - Gabrielsen, Maiken E.

AU - Schmidt, Ellen M.

AU - Beaumont, Robin

AU - Wolford, Brooke N.

AU - Lin, Maoxuan

AU - Brummett, Chad M.

AU - Preuss, Michael H.

AU - Refsgaard, Lena

AU - Bottinger, Erwin P.

AU - Graham, Sarah E.

AU - Surakka, Ida

AU - Chu, Yunhan

AU - Skogholt, Anne Heidi

AU - Dalen, Håvard

AU - Boyle, Alan P.

AU - Oral, Hakan

AU - Herron, Todd J.

AU - Kitzman, Jacob

AU - Jalife, José

AU - Svendsen, Jesper H.

AU - Olesen, Morten S.

AU - Njølstad, Inger

AU - Løchen, Maja Lisa

AU - Baras, Aris

AU - Gottesman, Omri

AU - Marcketta, Anthony

AU - O'Dushlaine, Colm

AU - Ritchie, Marylyn D.

AU - Wilsgaard, Tom

AU - Loos, Ruth J.F.

AU - Frayling, Timothy M.

AU - Boehnke, Michael

AU - Ingelsson, Erik

AU - Carey, David J.

AU - Dewey, Frederick E.

AU - Kang, Hyun M.

AU - Abecasis, Gonçalo R.

AU - Hveem, Kristian

AU - Willer, Cristen J.

PY - 2018/1/4

Y1 - 2018/1/4

N2 - Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

AB - Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

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