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Hum Mol Genet. 2017 May 1;26(9):1770-1784. doi: 10.1093/hmg/ddx062.

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.

Spracklen CN1, Chen P2,3, Kim YJ4, Wang X5, Cai H6, Li S7, Long J6, Wu Y1, Wang YX8, Takeuchi F9, Wu JY10,11, Jung KJ12, Hu C13, Akiyama K9, Zhang Y14, Moon S4, Johnson TA15, Li H16, Dorajoo R17, He M18, Cannon ME1, Roman TS1, Salfati E19, Lin KH20, Guo X21, Sheu WHH22,23,24,25, Absher D26, Adair LS27, Assimes TL19, Aung T28,29,30, Cai Q6, Chang LC10, Chen CH10,11, Chien LH31, Chuang LM32,33,34, Chuang SC31, Du S27,35, Fan Q28, Fann CSJ10, Feranil AB36,37, Friedlander Y38, Gordon-Larsen P27,35, Gu D39, Gui L18, Guo Z14, Heng CK40,41, Hixson J42, Hou X13, Hsiung CA31, Hu Y16, Hwang MY4, Hwu CM23,43, Isono M9, Juang JJ33,44, Khor CC17,45, Kim YK4, Koh WP2,29, Kubo M46, Lee IT22,23,47, Lee SJ12, Lee WJ48,49, Liang KW23,50,51, Lim B28, Lim SH28, Liu J2,17,52, Nabika T53, Pan WH10, Peng H14, Quertermous T19, Sabanayagam C28,29, Sandow K21, Shi J54, Sun L16, Tan PC28, Tan SP28, Taylor KD21, Teo YY2,5,17,55,56, Toh SA52, Tsunoda T15,57, van Dam RM2, Wang A14, Wang F16, Wang J13, Wei WB58, Xiang YB59, Yao J21, Yuan JM60,61, Zhang R13, Zhao W28,29, Chen YI21, Rich SS62, Rotter JI21, Wang TD33,44, Wu T18, Lin X16, Han BG63, Tanaka T64,65, Cho YS66, Katsuya T67, Jia W13, Jee SH12, Chen YT10, Kato N9, Jonas JB8,68, Cheng CY28,29,30, Shu XO6, He J7, Zheng W6, Wong TY28,29,30, Huang W54, Kim BJ4, Tai ES2,29,52, Mohlke KL1, Sim X2.

Author information

1
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
2
Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore.
3
Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
4
Division of Structural and Functional Genomics, Center for Genome Science, Korean National Institute of Health, Osong, Chungchungbuk-do, South Korea.
5
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
6
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
7
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
8
Beijing Institute of Ophthalmology, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
9
National Center for Global Health and Medicine, Tokyo, Japan.
10
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
11
School of Chinese Medicine, China Medical University, Taichung, Taiwan.
12
Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea.
13
Shanghai Diabetes Institute, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
14
Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China.
15
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
16
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
17
Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
18
Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
19
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
20
Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan.
21
Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
22
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
23
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
24
School of Medicine, National Defense Medical Center, Taipei, Taiwan.
25
Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan.
26
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
27
Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
28
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
29
Duke-NUS Medical School Singapore, Singapore, Singapore.
30
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
31
Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
32
Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
33
College of Medicine, National Taiwan University, Taipei, Taiwan.
34
Institute of Preventive Medicine, School of Public Health, National Taiwan University, Taipei, Taiwan.
35
Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
36
USC-Office of Population Studies Foundation, Inc, University of San Carlos, Cebu City, Philippines.
37
Department of Anthropology, Sociology, and History, University of San Carlos, Cebu City, Philippines.
38
Unit of Epidemiology, Hebrew University-Hadassah Braun School of Public Health, Jerusalem, Israel.
39
Department of Epidemiology and Population Genetics, Fuwai Hospital, Beijing, China.
40
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
41
Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
42
Human Genetics Center, University of Texas School of Public Health, Houston, TX, USA.
43
Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
44
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
45
Department of Biochemistry, National University of Singapore, Singapore, Singapore.
46
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
47
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
48
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
49
Department of Social Work, Tunghai University, Taichung, Taiwan.
50
Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
51
Department of Medicine, China Medical University, Taichung, Taiwan.
52
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
53
Department of Functional Pathology, Shimane University School of Medicine, Izumo, Japan.
54
Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute, Shanghai, China.
55
NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore.
56
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
57
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
58
Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology and Visual Science Key Lab, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Capital Medical University, Beijing, China.
59
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
60
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
61
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
62
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
63
Center for Genome Science, Korean National Institute of Health, Osong, Chungchungbuk-do, South Korea.
64
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
65
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
66
Department of Biomedical Science, Hallym University, Chuncheon, South Korea.
67
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
68
Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.

Abstract

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

PMID:
28334899
PMCID:
PMC6075203
DOI:
10.1093/hmg/ddx062
[Indexed for MEDLINE]
Free PMC Article

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