Abstract

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10−8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10−7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

  2. 2.

    et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).

  3. 3.

    et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008).

  4. 4.

    et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).

  5. 5.

    et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  6. 6.

    et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat. Genet. 41, 157–159 (2009).

  7. 7.

    et al. Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet. 6, e1000916 (2010).

  8. 8.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

  9. 9.

    et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716–718 (2008).

  10. 10.

    Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).

  11. 11.

    et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009).

  12. 12.

    , & Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes. Rev. 3, 141–146 (2002).

  13. 13.

    et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).

  14. 14.

    W.H.O. Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363, 157–163 (2004).

  15. 15.

    et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

  16. 16.

    et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

  17. 17.

    et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 (2007).

  18. 18.

    et al. BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1. Diabetes 59, 2063–2067 (2010).

  19. 19.

    et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 4, e1000214 (2008).

  20. 20.

    et al. Common variants at CDKAL1 and KLF9 loci are associated with body mass index in east Asian populations. Nat. Genet. published online, doi:10.1038ng.1086 (12 February 2012).

  21. 21.

    et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat. Genet. 40, 943–945 (2008).

  22. 22.

    et al. TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res. 28, 316–319 (2000).

  23. 23.

    et al. SCAN: SNP and copy number annotation. Bioinformatics 26, 259–262 (2010).

  24. 24.

    et al. Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J. Clin. Endocrinol. Metab. 89, 5043–5047 (2004).

  25. 25.

    et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).

  26. 26.

    & Meta-analysis in genome-wide association studies. Pharmacogenomics 10, 191–201 (2009).

  27. 27.

    The combination of estimates from different experiments. Biometrics 10, 101–129 (1954).

  28. 28.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  29. 29.

    et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 42, 570–575 (2010).

  30. 30.

    & SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 37, W600–W605 (2009).

  31. 31.

    , & Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

  32. 32.

    et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

  33. 33.

    et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2011).

  34. 34.

    et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  35. 35.

    , & Structural variation in the human genome. Nat. Rev. Genet. 7, 85–97 (2006).

Download references

Acknowledgements

The Shanghai Genome Wide Associations Studies (SGWAS) would like to thank the dedicated investigators and staff members from the research teams at Vanderbilt University, the Shanghai Cancer Institute and the Shanghai Institute of Preventive Medicine and, most of all, the study participants for their contributions to this work. Genotyping assays and statistical analyses for the SGWAS were primarily supported by grants from the US National Institutes of Health (NIH; R01 CA064277, R37 CA070867, R01 CA090899, R01 CA118229, R01 CA092585 and R01 CA122756), as well as by Ingram professorship funds, Allen Foundation funds and a Vanderbilt Clinical and Translational Science Award (CTSA; 1 UL1 RR024975) from the National Center for Research Resources (NCRR) at the NIH. NIH grants provided support for the participating studies, including the Shanghai Breast Cancer Study (R01 CA064277), the Shanghai Breast Cancer Survival Study (R01 CA118229) and the Shanghai Endometrial Cancer Study (R01 CA092585). The KARE project was supported by grants from the Korea Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307). The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC; 05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC; NMRC/1174/2008). E.S.T. also received support from the NMRC through a clinician scientist award (NMRC/CSA/008/2009). The Singapore Malay Eye Study (SiMES) was funded by the NMRC (NMRC/0796/2003 and NMRC/STaR/0003/2008) and the BMRC (09/1/35/19/616). The CAGE Network Studies were supported by grants for the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency, the Program for Promotion of Fundamental Studies in Health Sciences, the National Institute of Biomedical Innovation Organization (NIBIO) and the National Center for Global Health and Medicine (NCGM). L.Q. is supported by a grant from the NIH (HL071981), an American Heart Association Scientist Development Award and the Boston Obesity Nutrition Research Center (DK46200). The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by research grants from the National Heart, Lung, and Blood Institute at the NIH (HL072507, HL087263 and HL090682). SINDI was funded by grants from the BMRC (09/1/35/19/616 and 08/1/35/19/550) and the NMRC (NMRC/STaR/0003/2008). SCORM was funded by the NMRC (NMRC/0975/2005), the BMRC (06/1/21/19/466) and the Centre for Molecular Epidemiology at the National University of Singapore. The SIH was supported by the Chinese National Key Program for Basic Research (973:2004CB518603) and the Chinese National High Tech Program (863:2009AA022703). The MEC was supported by grants from the National Cancer Institute (NCI; CA063464, CA054281 and CA132839) and from the NIH Genes, Environment and Health Initiative (GEI; HG004726). Assistance with genotype cleaning for the MEC Japanese prostate cancer study was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard University, was provided by the GEI (HG04424).

Author information

Author notes

    • Wanqing Wen
    • , Yoon-Shin Cho
    • , Wei Zheng
    • , Rajkumar Dorajoo
    • , Norihiro Kato
    • , Lu Qi
    •  & Chien-Hsiun Chen

    These authors contributed equally to this work.

    • Jer-Yuarn Wu
    • , Jong-Young Lee
    • , Frank B Hu
    • , Toshihiro Tanaka
    • , E Shyong Tai
    •  & Xiao-Ou Shu

    These authors jointly directed this work.

Affiliations

  1. Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Wanqing Wen
    • , Wei Zheng
    • , Ryan J Delahanty
    • , Jirong Long
    • , Qiuyin Cai
    • , Jiajun Shi
    •  & Xiao-Ou Shu
  2. Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Wanqing Wen
    • , Wei Zheng
    • , Ryan J Delahanty
    • , Jirong Long
    • , Qiuyin Cai
    • , Jiajun Shi
    •  & Xiao-Ou Shu
  3. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Wanqing Wen
    • , Wei Zheng
    • , Ryan J Delahanty
    • , Jirong Long
    • , Qiuyin Cai
    • , Jiajun Shi
    •  & Xiao-Ou Shu
  4. Center for Genome Science, National Institute of Health, Cheongwon-gun, Republic of Korea.

    • Yoon-Shin Cho
    • , Min-Jin Go
    • , Bok-Ghee Han
    •  & Jong-Young Lee
  5. Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea.

    • Yoon-Shin Cho
  6. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

    • Rajkumar Dorajoo
    • , Rick T H Ong
    • , Jian-Jun Liu
    •  & Mark Seielstad
  7. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Rajkumar Dorajoo
  8. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

    • Norihiro Kato
    •  & Fumihiko Takeuchi
  9. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lu Qi
    •  & Frank B Hu
  10. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Chien-Hsiun Chen
    • , Li-Ching Chang
    • , Mei-Hsin Su
    • , Cathy S J Fann
    •  & Jer-Yuarn Wu
  11. School of Chinese Medicine, China Medical University, Taichung, Taiwan.

    • Chien-Hsiun Chen
    • , Fuu-Jen Tsai
    •  & Jer-Yuarn Wu
  12. Laboratory for Statistical Analysis, Center for Genomic Medicine (CGM), RIKEN, Yokohama, Japan.

    • Yukinori Okada
    •  & Naoyuki Kamatani
  13. Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

    • Yukinori Okada
  14. Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon, Japan.

    • Yasuharu Tabara
  15. Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Dongfeng Gu
  16. State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Dingliang Zhu
    •  & Yi Zhang
  17. Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Dingliang Zhu
    •  & Yi Zhang
  18. Sino-French Research Center for Life Science and Genomics, Shanghai, China.

    • Dingliang Zhu
    •  & Yi Zhang
  19. Shanghai Key Laboratory of Vascular Biology, Shanghai, China.

    • Dingliang Zhu
  20. Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Christopher A Haiman
    • , Brian E Henderson
    •  & Gary K Chen
  21. Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, China.

    • Zengnan Mo
  22. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
    •  & Yong-Bing Xiang
  23. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Seang-Mei Saw
    • , Daniel P-K Ng
    •  & E Shyong Tai
  24. Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Yoshihiro Kokubo
  25. Department of Endocrinology, The Central Hospital of Xuzhou, Affiliated Hospital of Southeast University, Xuzhou, China.

    • Jun Liang
  26. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.

    • Mei Hao
    •  & Jiang He
  27. Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, USA.

    • Loïc Le Marchand
  28. Medical Scientific Research Center, Guangxi Medical University, Nanning, China.

    • Yanling Hu
  29. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Tien-Yin Wong
    •  & Tin Aung
  30. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Tien-Yin Wong
    •  & Tin Aung
  31. Center for Eye Research Australia, The University of Melbourne, East Melbourne, Victoria, Australia.

    • Tien-Yin Wong
  32. Laboratory for Genotyping Development, CGM, RIKEN, Yokohama, Japan.

    • Michiaki Kubo
  33. Division of Genome Analysis, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

    • Ken Yamamoto
  34. Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Japan.

    • Tetsuro Miki
  35. State Key Laboratory of Medical Genomics, Molecular Medical Center, Shanghai Institute of Endocrinology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Huaidong Song
  36. Center for Metabolic Disease and Diabetes, First Affiliated Hospital of Guangxi Medical University, Nanning, China.

    • Aihua Tan
  37. Laboratory for Medical Informatics, CGM, RIKEN, Yokohama, Japan.

    • Tatsuhiko Tsunoda
  38. Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Naoharu Iwai
  39. Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Jianfeng Xu
  40. Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Xueling Sim
  41. Laboratory for Endocrinology and Metabolism, CGM, RIKEN, Yokohama, Japan.

    • Shiro Maeda
  42. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.

    • Rick T H Ong
  43. Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Chun Li
  44. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

    • Yusuke Nakamura
  45. Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.

    • Wei Lu
  46. Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan.

    • Mitsuhiro Yokota
  47. Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

    • Mark Seielstad
  48. Department of Epidemiology, Harvard University School of Public Health, Boston, Massachusetts, USA.

    • Frank B Hu
  49. Laboratory for Cardiovascular Diseases, CGM, RIKEN, Yokohama, Japan.

    • Toshihiro Tanaka
  50. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  51. Duke–National University of Singapore Graduate Medical School, Singapore.

    • E Shyong Tai

Consortia

  1. The Genetic Investigation of ANthropometric Traits (GIANT) Consortium

    A complete list of authors is provided in the Supplementary Note.

Authors

  1. Search for Wanqing Wen in:

  2. Search for Yoon-Shin Cho in:

  3. Search for Wei Zheng in:

  4. Search for Rajkumar Dorajoo in:

  5. Search for Norihiro Kato in:

  6. Search for Lu Qi in:

  7. Search for Chien-Hsiun Chen in:

  8. Search for Ryan J Delahanty in:

  9. Search for Yukinori Okada in:

  10. Search for Yasuharu Tabara in:

  11. Search for Dongfeng Gu in:

  12. Search for Dingliang Zhu in:

  13. Search for Christopher A Haiman in:

  14. Search for Zengnan Mo in:

  15. Search for Yu-Tang Gao in:

  16. Search for Seang-Mei Saw in:

  17. Search for Min-Jin Go in:

  18. Search for Fumihiko Takeuchi in:

  19. Search for Li-Ching Chang in:

  20. Search for Yoshihiro Kokubo in:

  21. Search for Jun Liang in:

  22. Search for Mei Hao in:

  23. Search for Loïc Le Marchand in:

  24. Search for Yi Zhang in:

  25. Search for Yanling Hu in:

  26. Search for Tien-Yin Wong in:

  27. Search for Jirong Long in:

  28. Search for Bok-Ghee Han in:

  29. Search for Michiaki Kubo in:

  30. Search for Ken Yamamoto in:

  31. Search for Mei-Hsin Su in:

  32. Search for Tetsuro Miki in:

  33. Search for Brian E Henderson in:

  34. Search for Huaidong Song in:

  35. Search for Aihua Tan in:

  36. Search for Jiang He in:

  37. Search for Daniel P-K Ng in:

  38. Search for Qiuyin Cai in:

  39. Search for Tatsuhiko Tsunoda in:

  40. Search for Fuu-Jen Tsai in:

  41. Search for Naoharu Iwai in:

  42. Search for Gary K Chen in:

  43. Search for Jiajun Shi in:

  44. Search for Jianfeng Xu in:

  45. Search for Xueling Sim in:

  46. Search for Yong-Bing Xiang in:

  47. Search for Shiro Maeda in:

  48. Search for Rick T H Ong in:

  49. Search for Chun Li in:

  50. Search for Yusuke Nakamura in:

  51. Search for Tin Aung in:

  52. Search for Naoyuki Kamatani in:

  53. Search for Jian-Jun Liu in:

  54. Search for Wei Lu in:

  55. Search for Mitsuhiro Yokota in:

  56. Search for Mark Seielstad in:

  57. Search for Cathy S J Fann in:

  58. Search for Jer-Yuarn Wu in:

  59. Search for Jong-Young Lee in:

  60. Search for Frank B Hu in:

  61. Search for Toshihiro Tanaka in:

  62. Search for E Shyong Tai in:

  63. Search for Xiao-Ou Shu in:

Contributions

T.A., Y.-S.C., Y.-T.G., D.G., B.-G.H., J.H., F.B.H., N. Kamatani, N. Kato, L.-L.-M., J.-Y.L., W.L., Z.M., Y.N., D.P.-K.N., L.Q., S.-M.S., X.-O.S., E.-S.T., F.-J.T., T. Tanaka, F.J.T., T.-Y.W., J.-Y.W., Y.-B.X., J.X., W.Z. and D.Z. supervised the research. Y.-S.C., D.G., J.H., Y.H., N. Kato, J. Liang, Z.M., Y.N., L.Q., M.S., X.-O.S., H.S., E.S.T., T. Tanaka, T.-Y.W., W.Z. and D.Z. conceived and designed the experiments. J.H., Y.H., M.K., J. Liang, M.S., J.S., M.Y. and Y.Z. performed the experiments. L.-C.C., C.-H.C., G.K.C., R.D., M.-J.G., M.H., Y.H., C.L., J. Long, Y.O., L.Q., M.-H.S., Y.T., A.T., T. Tsunoda and W.W. performed the statistical analyses. The GIANT Consortium, Q.C., L.-C.C., C.-H.C., R.J.D., R.D., M.-J.G., M.H., Y.H., N.I., J. Long, T.M., Y.O., R.T.H.O., L.Q., X.S., M.-H.S. and Y.T. analyzed the data. T.A., Q.C., Y.-T.G., C.A.H., B.E.H., N.I., N. Kato, Y.K., L.L.-M., J. Liang, J.-J.L., W.L., D.P.-K.N., L.Q., S.-M.S., M.S., X.-O.S., H.S., E.S.T., F.-J.T., T.-Y.W., J.-Y.W., Y.-B.X., K.Y., M.Y., C.S.J.F. and W.Z. contributed reagents, materials and/or analysis tools. R.J.D., Y.O., X.-O.S., E.S.T., T. Tanaka, W.W. and W.Z. wrote the manuscript. S.M. reviewed the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xiao-Ou Shu.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figure 1, Supplementary Table 1–10 and Supplementary Note

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.1087

Further reading