期刊
NATURE GENETICS
卷 45, 期 5, 页码 513-U76出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2607
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资金
- Wellcome Trust [084713, WT098051]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Medical Research Council UK
- Cancer Research UK
- MRC [MC_U106188470, G0600717, MC_UU_12015/1, MC_UU_12012/1, G0900554, G9824984] Funding Source: UKRI
- Medical Research Council [G0900554, MC_UU_12012/1, MC_UU_12015/1, G0600717, MC_UU_12012/5/B, G0600717B, MC_U106188470, MC_U106179471, G9824984] Funding Source: researchfish
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 x 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 x 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 x 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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