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Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population

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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.

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Abbreviations

AF:

Atrial fibrillation

HCM:

Hypertrophic cardiomyopathy

TNNI3:

Cardiac troponin I

SIFT:

Sorting intolerant from tolerant

PROVEAN:

Protein variation effect analyzer

SNPs:

Single-nucleotide polymorphisms

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Acknowledgments

We are grateful for study subjects for their participation of this project. We thank current and previous members of Wang laboratory for help and technical assistance in GeneID.

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    Authors and Affiliations

    1. 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

      Chuchu Wang, Manman Wu, Xin Tu, Chengqi Xu, Sisi Li, Shanshan Chen, Yuanyuan Zhao, Yufeng Huang, Lisong Shi & Qing K. Wang

    2. Central Hospital of Suizhou City, Suizhou, 441300, China

      Jin Qian & Wei Yao

    3. Xiang Yang Central Hospital, Xiangyang, 441021, China

      Bin Li

    4. Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

      Xiang Cheng & Yuhua Liao

    5. Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

      Yunlong Xia

    6. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

      Gang Wu

    7. Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

      Mian Cheng

    8. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA

      Qiuyun Chen & Qing K. Wang

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    1. Chuchu Wang
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    Correspondence to Qing K. Wang.

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    Funding

    This study was supported by the China National Natural Science Foundation Key Program (31430047), Chinese National Basic Research Programs (973 Programs 2013CB531101 and 2012CB517801), Hubei Province’s Outstanding Medical Academic Leader Program, Hubei Province Natural Science Key Program (2014CFA074), the China National Natural Science Foundation Grant (91439129, NSFC-J1103514), NIH/NHLBI Grants R01 HL121358 and R01 HL126729, Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education, and the “Innovative Development of New Drugs” Key Scientific Project (2011ZX09307-001-09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Conflict of interest

    Chuchu Wang declares that she has no conflict of interest. Manman Wu declares that she has no conflict of interest. Jin Qian declares that he has no conflict of interest. Bin Li declares that he has no conflict of interest. Chengqi Xu declares that he has no conflict of interest. Sisi Li declares that she has no conflict of interest. Shanshan Chen declares that she has no conflict of interest. Yuanyuan Zhao declares that she has no conflict of interest. Yufeng Huang declares that she has no conflict of interest. Lisong Shi declares that he has no conflict of interest. Xiang Cheng declares that he has no conflict of interest. Yuhua Liao declares that he has no conflict of interest. Qiuyun Chen declares that he has no conflict of interest. Yunlong Xia declares that he has no conflict of interest. Wei Yao declares that he has no conflict of interest. Gang Wu declares that he has no conflict of interest. Mian Cheng declares that she has no conflict of interest. Qing K. Wang declares that he has no conflict of interest.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of College of Life Science and Technology, Huazhong University of Science and Technology and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

    Informed consent

    Informed consent was obtained from all individual participants included in the study.

    Additional information

    Communicated by S. Hohmann.

    C. Wang, M. Wu, J. Qian, B. Li, X. Tu, and C. Xu contributed equally to this work.

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    Wang, C., Wu, M., Qian, J. et al. Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population. Mol Genet Genomics 291, 79–92 (2016). https://doi.org/10.1007/s00438-015-1090-y

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