Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify ge...

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Published in:JAMA : the journal of the American Medical Association 2018-12, Vol.320 (22), p.2354-2364
Main Authors: Choi, Seung Hoan, Weng, Lu-Chen, Roselli, Carolina, Lin, Honghuang, Haggerty, Christopher M, Shoemaker, M. Benjamin, Barnard, John, Arking, Dan E, Chasman, Daniel I, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Smith, Jonathan D, Gupta, Namrata, Gabriel, Stacey, Margolin, Lauren, Shea, Marisa A, Shaffer, Christian M, Yoneda, Zachary T, Boerwinkle, Eric, Smith, Nicholas L, Silverman, Edwin K, Redline, Susan, Vasan, Ramachandran S, Burchard, Esteban G, Gogarten, Stephanie M, Laurie, Cecelia, Blackwell, Thomas W, Abecasis, Gonçalo, Carey, David J, Fornwalt, Brandon K, Smelser, Diane T, Baras, Aris, Dewey, Frederick E, Jaquish, Cashell E, Papanicolaou, George J, Sotoodehnia, Nona, Van Wagoner, David R, Psaty, Bruce M, Kathiresan, Sekar, Darbar, Dawood, Alonso, Alvaro, Heckbert, Susan R, Chung, Mina K, Roden, Dan M, Benjamin, Emelia J, Murray, Michael F, Lunetta, Kathryn L, Lubitz, Steven A, Ellinor, Patrick T
Format: Article
Language:English
Subjects:
Adult
Age
Age of Onset
Arrhythmia
Atrial Fibrillation - genetics
Cardiac arrhythmia
Case-Control Studies
Connectin
Connectin - genetics
Correlation analysis
Female
Fibrillation
Gene sequencing
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genome-Wide Association Study
Genomes
Heart
Heterozygote
Humans
Loss of Function Mutation
Lungs
Male
Middle Aged
Patients
Precision medicine
Proteins
Quality Control
Statistical analysis
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cited_by cdi_FETCH-LOGICAL-a506t-812c292fbcbbd5db283588d7a6db1b83dca44dc14ac85692d08333d804ac224d3
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container_issue 22
container_start_page 2354
container_title JAMA : the journal of the American Medical Association
container_volume 320
creator Choi, Seung Hoan
Weng, Lu-Chen
Roselli, Carolina
Lin, Honghuang
Haggerty, Christopher M
Shoemaker, M. Benjamin
Barnard, John
Arking, Dan E
Chasman, Daniel I
Albert, Christine M
Chaffin, Mark
Tucker, Nathan R
Smith, Jonathan D
Gupta, Namrata
Gabriel, Stacey
Margolin, Lauren
Shea, Marisa A
Shaffer, Christian M
Yoneda, Zachary T
Boerwinkle, Eric
Smith, Nicholas L
Silverman, Edwin K
Redline, Susan
Vasan, Ramachandran S
Burchard, Esteban G
Gogarten, Stephanie M
Laurie, Cecelia
Blackwell, Thomas W
Abecasis, Gonçalo
Carey, David J
Fornwalt, Brandon K
Smelser, Diane T
Baras, Aris
Dewey, Frederick E
Jaquish, Cashell E
Papanicolaou, George J
Sotoodehnia, Nona
Van Wagoner, David R
Psaty, Bruce M
Kathiresan, Sekar
Darbar, Dawood
Alonso, Alvaro
Heckbert, Susan R
Chung, Mina K
Roden, Dan M
Benjamin, Emelia J
Murray, Michael F
Lunetta, Kathryn L
Lubitz, Steven A
Ellinor, Patrick T
description IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons
doi_str_mv 10.1001/jama.2018.18179
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Benjamin ; Barnard, John ; Arking, Dan E ; Chasman, Daniel I ; Albert, Christine M ; Chaffin, Mark ; Tucker, Nathan R ; Smith, Jonathan D ; Gupta, Namrata ; Gabriel, Stacey ; Margolin, Lauren ; Shea, Marisa A ; Shaffer, Christian M ; Yoneda, Zachary T ; Boerwinkle, Eric ; Smith, Nicholas L ; Silverman, Edwin K ; Redline, Susan ; Vasan, Ramachandran S ; Burchard, Esteban G ; Gogarten, Stephanie M ; Laurie, Cecelia ; Blackwell, Thomas W ; Abecasis, Gonçalo ; Carey, David J ; Fornwalt, Brandon K ; Smelser, Diane T ; Baras, Aris ; Dewey, Frederick E ; Jaquish, Cashell E ; Papanicolaou, George J ; Sotoodehnia, Nona ; Van Wagoner, David R ; Psaty, Bruce M ; Kathiresan, Sekar ; Darbar, Dawood ; Alonso, Alvaro ; Heckbert, Susan R ; Chung, Mina K ; Roden, Dan M ; Benjamin, Emelia J ; Murray, Michael F ; Lunetta, Kathryn L ; Lubitz, Steven A ; Ellinor, Patrick T</creator><creatorcontrib>Choi, Seung Hoan ; Weng, Lu-Chen ; Roselli, Carolina ; Lin, Honghuang ; Haggerty, Christopher M ; Shoemaker, M. Benjamin ; Barnard, John ; Arking, Dan E ; Chasman, Daniel I ; Albert, Christine M ; Chaffin, Mark ; Tucker, Nathan R ; Smith, Jonathan D ; Gupta, Namrata ; Gabriel, Stacey ; Margolin, Lauren ; Shea, Marisa A ; Shaffer, Christian M ; Yoneda, Zachary T ; Boerwinkle, Eric ; Smith, Nicholas L ; Silverman, Edwin K ; Redline, Susan ; Vasan, Ramachandran S ; Burchard, Esteban G ; Gogarten, Stephanie M ; Laurie, Cecelia ; Blackwell, Thomas W ; Abecasis, Gonçalo ; Carey, David J ; Fornwalt, Brandon K ; Smelser, Diane T ; Baras, Aris ; Dewey, Frederick E ; Jaquish, Cashell E ; Papanicolaou, George J ; Sotoodehnia, Nona ; Van Wagoner, David R ; Psaty, Bruce M ; Kathiresan, Sekar ; Darbar, Dawood ; Alonso, Alvaro ; Heckbert, Susan R ; Chung, Mina K ; Roden, Dan M ; Benjamin, Emelia J ; Murray, Michael F ; Lunetta, Kathryn L ; Lubitz, Steven A ; Ellinor, Patrick T ; DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ; For the DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><description>IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons &lt;66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10−3. RESULTS: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10−4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10−5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). CONCLUSIONS AND RELEVANCE: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.</description><identifier>ISSN: 0098-7484</identifier><identifier>ISSN: 1538-3598</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.2018.18179</identifier><identifier>PMID: 30535219</identifier><language>eng</language><publisher>United States: American Medical Association</publisher><subject>Adult ; Age ; Age of Onset ; Arrhythmia ; Atrial Fibrillation - genetics ; Cardiac arrhythmia ; Case-Control Studies ; Connectin ; Connectin - genetics ; Correlation analysis ; Female ; Fibrillation ; Gene sequencing ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic variance ; Genome-Wide Association Study ; Genomes ; Heart ; Heterozygote ; Humans ; Loss of Function Mutation ; Lungs ; Male ; Middle Aged ; Patients ; Precision medicine ; Proteins ; Quality Control ; Statistical analysis</subject><ispartof>JAMA : the journal of the American Medical Association, 2018-12, Vol.320 (22), p.2354-2364</ispartof><rights>Copyright American Medical Association Dec 11, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a506t-812c292fbcbbd5db283588d7a6db1b83dca44dc14ac85692d08333d804ac224d3</citedby><cites>FETCH-LOGICAL-a506t-812c292fbcbbd5db283588d7a6db1b83dca44dc14ac85692d08333d804ac224d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,783,787,888,27938,27939</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30535219$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choi, Seung Hoan</creatorcontrib><creatorcontrib>Weng, Lu-Chen</creatorcontrib><creatorcontrib>Roselli, Carolina</creatorcontrib><creatorcontrib>Lin, Honghuang</creatorcontrib><creatorcontrib>Haggerty, Christopher M</creatorcontrib><creatorcontrib>Shoemaker, M. Benjamin</creatorcontrib><creatorcontrib>Barnard, John</creatorcontrib><creatorcontrib>Arking, Dan E</creatorcontrib><creatorcontrib>Chasman, Daniel I</creatorcontrib><creatorcontrib>Albert, Christine M</creatorcontrib><creatorcontrib>Chaffin, Mark</creatorcontrib><creatorcontrib>Tucker, Nathan R</creatorcontrib><creatorcontrib>Smith, Jonathan D</creatorcontrib><creatorcontrib>Gupta, Namrata</creatorcontrib><creatorcontrib>Gabriel, Stacey</creatorcontrib><creatorcontrib>Margolin, Lauren</creatorcontrib><creatorcontrib>Shea, Marisa A</creatorcontrib><creatorcontrib>Shaffer, Christian M</creatorcontrib><creatorcontrib>Yoneda, Zachary T</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Smith, Nicholas L</creatorcontrib><creatorcontrib>Silverman, Edwin K</creatorcontrib><creatorcontrib>Redline, Susan</creatorcontrib><creatorcontrib>Vasan, Ramachandran S</creatorcontrib><creatorcontrib>Burchard, Esteban G</creatorcontrib><creatorcontrib>Gogarten, Stephanie M</creatorcontrib><creatorcontrib>Laurie, Cecelia</creatorcontrib><creatorcontrib>Blackwell, Thomas W</creatorcontrib><creatorcontrib>Abecasis, Gonçalo</creatorcontrib><creatorcontrib>Carey, David J</creatorcontrib><creatorcontrib>Fornwalt, Brandon K</creatorcontrib><creatorcontrib>Smelser, Diane T</creatorcontrib><creatorcontrib>Baras, Aris</creatorcontrib><creatorcontrib>Dewey, Frederick E</creatorcontrib><creatorcontrib>Jaquish, Cashell E</creatorcontrib><creatorcontrib>Papanicolaou, George J</creatorcontrib><creatorcontrib>Sotoodehnia, Nona</creatorcontrib><creatorcontrib>Van Wagoner, David R</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Kathiresan, Sekar</creatorcontrib><creatorcontrib>Darbar, Dawood</creatorcontrib><creatorcontrib>Alonso, Alvaro</creatorcontrib><creatorcontrib>Heckbert, Susan R</creatorcontrib><creatorcontrib>Chung, Mina K</creatorcontrib><creatorcontrib>Roden, Dan M</creatorcontrib><creatorcontrib>Benjamin, Emelia J</creatorcontrib><creatorcontrib>Murray, Michael F</creatorcontrib><creatorcontrib>Lunetta, Kathryn L</creatorcontrib><creatorcontrib>Lubitz, Steven A</creatorcontrib><creatorcontrib>Ellinor, Patrick T</creatorcontrib><creatorcontrib>DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><creatorcontrib>For the DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</creatorcontrib><title>Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons &lt;66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10−3. RESULTS: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10−4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10−5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). CONCLUSIONS AND RELEVANCE: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.</description><subject>Adult</subject><subject>Age</subject><subject>Age of Onset</subject><subject>Arrhythmia</subject><subject>Atrial Fibrillation - genetics</subject><subject>Cardiac arrhythmia</subject><subject>Case-Control Studies</subject><subject>Connectin</subject><subject>Connectin - genetics</subject><subject>Correlation analysis</subject><subject>Female</subject><subject>Fibrillation</subject><subject>Gene sequencing</subject><subject>Genetic diversity</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic variance</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Heart</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Loss of Function Mutation</subject><subject>Lungs</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Patients</subject><subject>Precision medicine</subject><subject>Proteins</subject><subject>Quality Control</subject><subject>Statistical analysis</subject><issn>0098-7484</issn><issn>1538-3598</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkcFPHCEYxYmp0VV7buLBTNKLl1n5YJiBS5OtcVuTTbyoPRIG2MpmFhQYG__7srtqWrmQ8H7fy_d4CH0BPAWM4WKl1mpKMPApcOjEHpoAo7ymTPBPaIKx4HXX8OYQHaW0wuUA7Q7QIcWMMgJign7NUgraqeyCr77b_MdaX9267Hy1CCnVYVnPR6-38r2KTvmcKuVNdaXi8FLf-GRzNctFGKq566Mbhq3XCdpfqiHZz6_3MbqbX91e_qwXNz-uL2eLWjHc5poD0USQZa_73jDTE04Z56ZTremh59Ro1TRGQ6M0Z60gBnNKqeG4PBDSGHqMvu18H8d-bY22Pkc1yMfo1iq-yKCc_F_x7kH-Ds-ybWjLKC4G568GMTyNNmW5dknbEsPbMCZJgDFogYiuoF8_oKswRl_iFarFlFGBaaEudpSO5QOjXb4vA1huSpOb0uSmNLktrUyc_ZvhnX9rqQCnO2Az-KaSDjhuBf0L-MqcPg</recordid><startdate>20181211</startdate><enddate>20181211</enddate><creator>Choi, Seung Hoan</creator><creator>Weng, Lu-Chen</creator><creator>Roselli, Carolina</creator><creator>Lin, Honghuang</creator><creator>Haggerty, Christopher M</creator><creator>Shoemaker, M. 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Benjamin ; Barnard, John ; Arking, Dan E ; Chasman, Daniel I ; Albert, Christine M ; Chaffin, Mark ; Tucker, Nathan R ; Smith, Jonathan D ; Gupta, Namrata ; Gabriel, Stacey ; Margolin, Lauren ; Shea, Marisa A ; Shaffer, Christian M ; Yoneda, Zachary T ; Boerwinkle, Eric ; Smith, Nicholas L ; Silverman, Edwin K ; Redline, Susan ; Vasan, Ramachandran S ; Burchard, Esteban G ; Gogarten, Stephanie M ; Laurie, Cecelia ; Blackwell, Thomas W ; Abecasis, Gonçalo ; Carey, David J ; Fornwalt, Brandon K ; Smelser, Diane T ; Baras, Aris ; Dewey, Frederick E ; Jaquish, Cashell E ; Papanicolaou, George J ; Sotoodehnia, Nona ; Van Wagoner, David R ; Psaty, Bruce M ; Kathiresan, Sekar ; Darbar, Dawood ; Alonso, Alvaro ; Heckbert, Susan R ; Chung, Mina K ; Roden, Dan M ; Benjamin, Emelia J ; Murray, Michael F ; Lunetta, Kathryn L ; Lubitz, Steven A ; Ellinor, Patrick T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a506t-812c292fbcbbd5db283588d7a6db1b83dca44dc14ac85692d08333d804ac224d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Age</topic><topic>Age of Onset</topic><topic>Arrhythmia</topic><topic>Atrial Fibrillation - genetics</topic><topic>Cardiac arrhythmia</topic><topic>Case-Control Studies</topic><topic>Connectin</topic><topic>Connectin - genetics</topic><topic>Correlation analysis</topic><topic>Female</topic><topic>Fibrillation</topic><topic>Gene sequencing</topic><topic>Genetic diversity</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic variance</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Heart</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Loss of Function Mutation</topic><topic>Lungs</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Patients</topic><topic>Precision medicine</topic><topic>Proteins</topic><topic>Quality Control</topic><topic>Statistical analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choi, Seung Hoan</creatorcontrib><creatorcontrib>Weng, Lu-Chen</creatorcontrib><creatorcontrib>Roselli, Carolina</creatorcontrib><creatorcontrib>Lin, Honghuang</creatorcontrib><creatorcontrib>Haggerty, Christopher M</creatorcontrib><creatorcontrib>Shoemaker, M. 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Benjamin</au><au>Barnard, John</au><au>Arking, Dan E</au><au>Chasman, Daniel I</au><au>Albert, Christine M</au><au>Chaffin, Mark</au><au>Tucker, Nathan R</au><au>Smith, Jonathan D</au><au>Gupta, Namrata</au><au>Gabriel, Stacey</au><au>Margolin, Lauren</au><au>Shea, Marisa A</au><au>Shaffer, Christian M</au><au>Yoneda, Zachary T</au><au>Boerwinkle, Eric</au><au>Smith, Nicholas L</au><au>Silverman, Edwin K</au><au>Redline, Susan</au><au>Vasan, Ramachandran S</au><au>Burchard, Esteban G</au><au>Gogarten, Stephanie M</au><au>Laurie, Cecelia</au><au>Blackwell, Thomas W</au><au>Abecasis, Gonçalo</au><au>Carey, David J</au><au>Fornwalt, Brandon K</au><au>Smelser, Diane T</au><au>Baras, Aris</au><au>Dewey, Frederick E</au><au>Jaquish, Cashell E</au><au>Papanicolaou, George J</au><au>Sotoodehnia, Nona</au><au>Van Wagoner, David R</au><au>Psaty, Bruce M</au><au>Kathiresan, Sekar</au><au>Darbar, Dawood</au><au>Alonso, Alvaro</au><au>Heckbert, Susan R</au><au>Chung, Mina K</au><au>Roden, Dan M</au><au>Benjamin, Emelia J</au><au>Murray, Michael F</au><au>Lunetta, Kathryn L</au><au>Lubitz, Steven A</au><au>Ellinor, Patrick T</au><aucorp>DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</aucorp><aucorp>For the DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>2018-12-11</date><risdate>2018</risdate><volume>320</volume><issue>22</issue><spage>2354</spage><epage>2364</epage><pages>2354-2364</pages><issn>0098-7484</issn><issn>1538-3598</issn><eissn>1538-3598</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Acquisition, analysis, or interpretation of data: all authors</notes><notes>Additional Contribution</notes><notes>Drafting of the manuscript: Choi, Lunetta, Lubitz, Ellinor</notes><notes>Critical revision of the manuscript for important intellectual content: all authors</notes><notes>These authors contributed equally to the manuscript</notes><notes>Study concept and design: Choi, Lunetta, Lubitz, Ellinor</notes><notes>Statistical analysis: Choi, Weng, Haggerty</notes><notes>Study supervision: Lunetta, Lubitz, Ellinor</notes><notes>Author Contributions</notes><notes>Drs. Lunetta, Lubitz, and Ellinor contributed to the work equally. Dr. Ellinor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.</notes><notes>We thank all participants in the Geisinger MyCode Community Health Initiative. This research has been conducted using the UK Biobank Resource under Application Number 17488.</notes><abstract>IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons &lt;66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10−3. RESULTS: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10−4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10−5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). CONCLUSIONS AND RELEVANCE: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.</abstract><cop>United States</cop><pub>American Medical Association</pub><pmid>30535219</pmid><doi>10.1001/jama.2018.18179</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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issn 0098-7484
1538-3598
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language eng
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source AMA Current Titles
subjects Adult
Age
Age of Onset
Arrhythmia
Atrial Fibrillation - genetics
Cardiac arrhythmia
Case-Control Studies
Connectin
Connectin - genetics
Correlation analysis
Female
Fibrillation
Gene sequencing
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genome-Wide Association Study
Genomes
Heart
Heterozygote
Humans
Loss of Function Mutation
Lungs
Male
Middle Aged
Patients
Precision medicine
Proteins
Quality Control
Statistical analysis
title Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation
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