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

Abstract

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.

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Acknowledgements

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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Authors

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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.

Corresponding authors

Correspondence to Inês Barroso or I Sadaf Farooqi.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8 and Supplementary Tables 1–8 (PDF 1344 kb)

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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). https://doi.org/10.1038/ng.2607

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