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 language | English (US) |
|---|---|
| Pages (from-to) | 103-115 |
| Number of pages | 13 |
| Journal | American Journal of Human Genetics |
| Volume | 102 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 4 2018 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85039767541&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039767541&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.12.003
DO - 10.1016/j.ajhg.2017.12.003
M3 - Article
C2 - 29290336
AN - SCOPUS:85039767541
VL - 102
SP - 103
EP - 115
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -