Protein-Altering Variants Associated with Body Mass Index Implicate Pathways That Control Energy Intake and Expenditure in Obesity

Citation

Turcot, Valerie; Lu, Yingchang; Highland, Heather M.; Schurmann, Claudia; Justice, Anne E.; Fine, Rebecca S.; Bradfield, Jonathan P.; Esko, Tonu; Giri, Ayush; & Graff, Mariaelisa, et al. (2018). Protein-Altering Variants Associated with Body Mass Index Implicate Pathways That Control Energy Intake and Expenditure in Obesity. Nature Genetics, 50, 26-44. PMCID: PMC5945951

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.

URL

http://dx.doi.org/10.1038/s41588-017-0011-x

Reference Type

Journal Article

Year Published

2018

Journal Title

Nature Genetics

Series Title

V Turcot et al. Nat Genet 50 (5), 765-766. May 2018. PMID 29549329.
V Turcot et al. Nat Genet 50 (5), 766-767. May 2018. PMID 29549330.
V Turcot et al. Nat Genet 51 (7), 1191-1192. Jul 2019. PMID 31160809.

Author(s)

Turcot, Valerie
Lu, Yingchang
Highland, Heather M.
Schurmann, Claudia
Justice, Anne E.
Fine, Rebecca S.
Bradfield, Jonathan P.
Esko, Tonu
Giri, Ayush
Graff, Mariaelisa
Guo, Xiuqing
Hendricks, Audrey E.
Karaderi, Tugce
Lempradl, Adelheid
Locke, Adam E.
Mahajan, Anubha
Marouli, Eirini
Sivapalaratnam, Suthesh
Young, Kristin L.
Alfred, Tamuno
Feitosa, Mary F.
Masca, Nicholas G. D.
Manning, Alisa K.
Medina-Gomez, Carolina
Mudgal, Poorva
Ng, Maggie C. Y.
Reiner, Alexander P.
Vedantam, Sailaja
Willems, Sara M.
Winkler, Thomas W.
Abecasis, Gonçalo R.
Aben, Katja K.
Alam, Dewan S.
Alharthi, Sameer E.
Allison, Matthew A.
Amouyel, Philippe
Asselbergs, Folkert W.
Auer, Paul L.
Balkau, Beverley
Bang, Lia E.
Barroso, Ines
Bastarache, Lisa
Benn, Marianne
Bergmann, Sven
Bielak, Lawrence F.
Bluher, Matthias
Boehnke, Michael
Boeing, Heiner
Boerwinkle, Eric A.
Boger, Carsten A.
Bork-Jensen, Jette
Bots, Michiel L.
Bottinger, Erwin P.
Bowden, Donald W.
Brandslund, Ivan
Breen, Gerome
Brilliant, Murray H.
Broer, Linda
Brumat, Marco
Burt, Amber A.
Butterworth, Adam S.
Campbell, Peter T.
Cappellani, Stefania
Carey, David J.
Catamo, Eulalia
Caulfield, Mark J.
Chambers, John C.
Chasman, Daniel I.
Chen, Yii-Der Ida
Chowdhury, Rajiv
Christensen, Cramer
Chu, Audrey Y.
Cocca, Massimiliano
Collins, Francis S.
Cook, James P.
Corley, Janie
Corominas Galbany, Jordi
Cox, Amanda J.
Crosslin, David S.
Cuellar-Partida, Gabriel
D'Eustacchio, Angela
Danesh, John
Davies, Gail
Bakker, Paul I. W.
Groot, Mark C. H.
Mutsert, Renee
Deary, Ian J.
Dedoussis, George
Demerath, Ellen W.
Heijer, Martin
Hollander, Anneke I.
Ruijter, Hester M.
Dennis, Joe G.
Denny, Josh C.
Angelantonio, Emanuele
Drenos, Fotios
Du, Mengmeng
Dube, Marie-Pierre
Dunning, Alison M.
Easton, Douglas F.
Edwards, Todd L.
Ellinghaus, David
Ellinor, Patrick T.
Elliott, Paul
Evangelou, Evangelos
Farmaki, Aliki-Eleni
Farooqi, I. Sadaf
Faul, Jessica D.
Fauser, Sascha
Feng, Shuang
Ferrannini, Ele
Ferrieres, Jean
Florez, Jose C.
Ford, Ian
Fornage, Myriam
Franco, Oscar H.
Franke, Andre
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EPIC-CVD Consortium,
ExomeBP Consortium,
Global Lipids Genetics Consortium,
GoT2D Genes Consortium,
EPIC InterAct Consortium,
INTERVAL Study,
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T2D-Genes Consortium,
MAGIC Investigators,
Understanding Society Scientific Group,
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PMCID

PMC5945951

ORCiD

Gordon-Larsen - 0000-0001-5322-4188