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Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity


Common and rare variants associated with body mass index (BMI) and obesity account for <5% of the variance in BMI. We performed SNP and copy number variation (CNV) association analyses in 1,509 children with obesity at the extreme tail (>3 s.d. from the mean) of the BMI distribution and 5,380 controls. Evaluation of 29 SNPs (P < 1 × 10−5) in an additional 971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity (LEPR, PRKCH, PACS1 and RMST). A previously reported 43-kb deletion at the NEGR1 locus was significantly associated with severe obesity (P = 6.6 × 10−7). However, this signal was entirely driven by a flanking 8-kb deletion; absence of this deletion increased risk for obesity (P = 6.1 × 10−11). We found a significant burden of rare, single CNVs in severely obese cases (P < 0.0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein–coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis.

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Figure 1: Genome-wide SNP association study in severe early-onset obesity.
Figure 2: Regional association plots of the new loci.
Figure 3: A quantile-quantile plot of −log10 (P value) of 481 common CNVs.
Figure 4: NEGR1 locus on chromosome 1p31.1.


  1. Farooqi, I.S. & O'Rahilly, S. Genetic factors in human obesity. Obes. Rev. 8 (suppl. 1), 37–40 (2007).

    Article  Google Scholar 

  2. Loos, R.J. Genetic determinants of common obesity and their value in prediction. Best Pract. Res. Clin. Endocrinol. Metab. 26, 211–226 (2012).

    CAS  Article  Google Scholar 

  3. Zuk, O., Hechter, E., Sunyaev, S.R. & Lander, E.S. The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA 109, 1193–1198 (2012).

    CAS  Article  Google Scholar 

  4. Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    CAS  Article  Google Scholar 

  5. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  6. Stranger, B.E. et al. Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 8, e1002639 (2012).

    CAS  Article  Google Scholar 

  7. Bradfield, J.P. et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat. Genet. 44, 526–531 (2012).

    CAS  Article  Google Scholar 

  8. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    CAS  Article  Google Scholar 

  9. Frayling, T.M. 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).

    CAS  Article  Google Scholar 

  10. Scherag, A. 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).

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  12. Jiao, H. et al. Genome wide association study identifies KCNMA1 contributing to human obesity. BMC Med. Genomics 4, 51 (2011).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  14. Meyre, D. 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).

    CAS  Article  Google Scholar 

  15. Ichimura, A. et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012).

    CAS  Article  Google Scholar 

  16. Paternoster, L. et al. Genome-wide population-based association study of extremely overweight young adults—the GOYA study. PLoS ONE 6, e24303 (2011).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  18. Hafler, B.P., Choi, M.Y., Shivdasani, R.A. & Rowitch, D.H. Expression and function of Nkx6.3 in vertebrate hindbrain. Brain Res. 1222, 42–50 (2008).

    CAS  Article  Google Scholar 

  19. Schäfer, M., Brauer, A.U., Savaskan, N.E., Rathjen, F.G. & Brummendorf, T. Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion. Mol. Cell Neurosci. 29, 580–590 (2005).

    Article  Google Scholar 

  20. Bochukova, E.G. et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666–670 (2010).

    CAS  Article  Google Scholar 

  21. Stice, E., Spoor, S., Bohon, C. & Small, D.M. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science 322, 449–452 (2008).

    CAS  Article  Google Scholar 

  22. Raychaudhuri, S. et al. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 6, pii: e1001097 (2010).

    Article  Google Scholar 

  23. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    CAS  Article  Google Scholar 

  24. Day, N. et al. EPIC –Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer 80 (suppl. 1), 95–103 (1999).

    PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

  26. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome –wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    CAS  Article  Google Scholar 

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We are indebted to the subjects and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS). The authors would like to thank S. Edkins, E. Gray, D. Simpkin, S. Hunt, S. Bumpstead and S. Dronov of the WTSI Sample Logistics, Genotyping and Variation Informatics Facilities; F. Payne and E. Gayton for TaqMan genotyping; and E. Gonçalves Serra for imputation of the GPR120 region. This work was supported by the Wellcome Trust (084713 and WT098051) and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The EPIC-Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2 (WTCCC2). A full list of the investigators who contributed to the generation of the data is available from the WTCCC website (see URLs).

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I.S.F., I.B., M.E.H., E.W., N.H. and E.G.B. designed the study, analyzed the data and wrote the manuscript. J.M.K., E.H., R.J.F.L., N.J.W. and S.O. were involved in the sample collection and phenotyping. S.L., S.G. and H.B. contributed to the genotyping and data analysis. All authors read, edited and approved the current version of the manuscript.

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Correspondence to Inês Barroso or I Sadaf Farooqi.

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The authors declare no competing financial interests.

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Wheeler, E., Huang, N., Bochukova, E. et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet 45, 513–517 (2013).

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