title: Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population.
abstract: Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as 'missing heritability'. One potential cause for 'missing heritability' is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by fivefold and doubles risk of heart failure and sudden death. Here, we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1127 unrelated AF patients and 1583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggest that rare TNNI3 variants are associated with AF (P = 0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability.
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Chuchu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Manman
authors.initials: M
authors.lastname: Wu
authors.affiliation: Central Hospital of Suizhou City, Suizhou, 441300, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.affiliation: Xiang Yang Central Hospital, Xiangyang, 441021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Chengqi
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Lisong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Central Hospital of Suizhou City, Suizhou, 441300, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. cheng.mian@icloud.com.
authors.forename: Mian
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. qkwang@hust.edu.cn.|Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA. qkwang@hust.edu.cn.
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D001281:Atrial Fibrillation / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007438:Introns / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D055815:Young Adult
chemical_list: D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases
keywords: Atrial fibrillation (AF); Cardiac troponin I; Hypertrophic cardiomyopathy; TNNI3 mutations; Whole exome sequencing