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Nat Genet. 2017 Dec;49(12):1722-1730. doi: 10.1038/ng.3978. Epub 2017 Oct 30.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.

Lu X1,2,3, Peloso GM4,5, Liu DJ6, Wu Y7, Zhang H2,3, Zhou W8, Li J9, Tang CS10, Dorajoo R11, Li H12, Long J13, Guo X14, Xu M15, Spracklen CN7, Chen Y16, Liu X9, Zhang Y17, Khor CC11,18,19, Liu J11, Sun L12, Wang L1, Gao YT20, Hu Y12, Yu K9, Wang Y12, Cheung CYY21, Wang F12, Huang J1,22, Fan Q19,23, Cai Q13, Chen S1, Shi J24, Yang X1, Zhao W19, Sheu WH25, Cherny SS26,27,28, He M9, Feranil AB29,30, Adair LS31, Gordon-Larsen P31,32, Du S31,32, Varma R33, Chen YI14, Shu XO13, Lam KSL21,34,35, Wong TY18,23,36,37, Ganesh SK2,3, Mo Z16, Hveem K38,39,40, Fritsche LG38,39,41, Nielsen JB2, Tse HF21,34,42, Huo Y17, Cheng CY19,37,43, Chen YE2, Zheng W13, Tai ES23,36,44, Gao W15, Lin X12, Huang W24, Abecasis G41; GLGC Consortium, Kathiresan S4,45, Mohlke KL7, Wu T9, Sham PC26,27,28, Gu D1, Willer CJ2,3,8.

Author information

1
Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
3
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
4
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
5
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
6
Department of Public Health Sciences, Institute of Personalized Medicine, Penn State University, University Park, Pennsylvania, USA.
7
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
8
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
9
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China.
10
Department of Surgery, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong, China.
11
Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
12
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and University of the Chinese Academy of Sciences, Shanghai, China.
13
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
14
Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Los Angeles, California, USA.
15
Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
16
Center for Genomic and Personalized Medicine, Medical Scientific Research Center and Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
17
Department of Cardiology, Peking University First Hospital, Beijing, China.
18
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore.
19
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
20
Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
21
Department of Medicine, the University of Hong Kong, Hong Kong, China.
22
Community Health Center, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, China.
23
Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
24
Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
25
Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
26
Department of Psychiatry, the University of Hong Kong, Hong Kong, China.
27
Centre for Genomic Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
28
State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
29
USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.
30
Department of Anthropology, Sociology, and History, University of San Carlos, Cebu City, Philippines.
31
Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
32
Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, USA.
33
USC Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
34
Research Centre of Heart, Brain, Hormone and Healthy Aging, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
35
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
36
Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore.
37
Department of Ophthalmology, National University of Singapore, Singapore, Singapore.
38
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
39
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
40
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
41
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
42
Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong, Hong Kong, China.
43
Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore.
44
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore.
45
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

PMID:
29083407
PMCID:
PMC5899829
DOI:
10.1038/ng.3978
[Indexed for MEDLINE]
Free PMC Article

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