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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada..
Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr,Vanderbilt Ep, Nashville, TN 37212 USA.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA.;Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Univ Texas Sch Publ Hlth, Univ Texas MD Anderson Canc Ctr,UTHealth Grad Sch, Houston, TX 77030 USA..
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 1, p. 26-+Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 50, no 1, p. 26-+
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Genetics
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URN: urn:nbn:se:uu:diva-343882DOI: 10.1038/s41588-017-0011-xISI: 000423157400007PubMedID: 29273807OAI: oai:DiVA.org:uu-343882DiVA, id: diva2:1191010
Funder
NIH (National Institute of Health), R01DK089256 R01DK101855 K99HL130580 R01DK106621 HL094535 HL109946 R01DK075787 R01HD057194 U01HG007416 1R01HL09257R01HL128914; K24HL105780; R01DK110113; U01HG007417; R01DK107786; K23HL114724EU, European Research Council, SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC; 323195; 293574Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved

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