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Rotter, JI and Pospisilik, JA and Rivadeneira, F and Borecki, IB and Deloukas, P and Frayling, TM and Lettre, G and North, KE and Lindgren, CM and Hirschhorn, JN and Loos, RJF (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. In: Nature Genetics, 50 (1). pp. 26-35.
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Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
| Item Type: | Journal Article |
|---|---|
| Publication: | Nature Genetics |
| Publisher: | Nature Publishing Group |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | acetylcholinesterase; protein, adult; animal experiment; animal tissue; Article; body mass; caloric intake; energy expenditure; ENTPD6 gene; female; gene control; gene frequency; gene identification; gene mutation; GIPR gene; HIP1R gene; human; KSR2 gene; major clinical study; male; MC4R gene; nonhuman; obesity; priority journal; PRKAG1 gene; RAB21 gene; RAPGEF3 gene; single nucleotide polymorphism; stop codon; ZBTB7B gene; ZFHX3 gene; ZFR2 gene; ZNF169 gene; animal; caloric intake; Drosophila; energy metabolism; genetic variation; genetics; obesity; syndrome, Adult; Animals; Body Mass Index; Drosophila; Energy Intake; Energy Metabolism; Female; Gene Frequency; Genetic Variation; Humans; Male; Obesity; Proteins; Syndrome |
| Department/Centre: | Autonomous Societies / Centres > Centre for Brain Research |
| Date Deposited: | 03 Sep 2022 03:59 |
| Last Modified: | 03 Sep 2022 03:59 |
| URI: | https://eprints.iisc.ac.in/id/eprint/76382 |
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