期刊
NATURE GENETICS
卷 40, 期 6, 页码 768-775出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.140
关键词
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资金
- British Heart Foundation Funding Source: Medline
- Cancer Research UK Funding Source: Medline
- Medical Research Council [MC_U106179472, U.1475.00.002.00001.01 (85824), G0600705, G0401527, MC_U105630924, G0000934, MC_QA137934, MC_U105161047, G0601261, G0600331, MC_UP_A620_1014, G9521010(63660), G0000934(68341), MC_U147585824, G9828345, MC_U106188470, G0400874, G9521010, G9824984, G0701863] Funding Source: Medline
- NIDDK NIH HHS [K23 DK080145, K23 DK080145-01, F32 DK079466, P30 DK040561, F32 DK079466-01, P30 DK040561-13, R01 DK072193] Funding Source: Medline
- Wellcome Trust [079557, 077016, 090532, 084713, 068545, 076113] Funding Source: Medline
- Department of Health [DHCS/07/07/008] Funding Source: Medline
- Medical Research Council [G0000934, U1475000001, G9828345, G0601261, G0600705, G9824984, MC_U105630924, MC_U106179472, MC_qA137934, G0400874, G9521010, MC_U106188470, MC_U147585824, G0600331, G0401527, G0701863, MC_U105161047] Funding Source: researchfish
- National Institute for Health Research [DHCS/07/07/008] Funding Source: researchfish
- MRC [MC_U106179472, MC_U106188470, G9828345, G0600331, G0601261, MC_U105630924, G0000934, G0400874, G0701863, G0600705, G9824984, MC_qA137934, G9521010, MC_U105161047] Funding Source: UKRI
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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