Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

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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 GD
Manning, Alisa K
Medina-Gomez, Carolina
Mudgal, Poorva
Ng, Maggie CY
Reiner, Alex P
Vedantam, Sailaja
Willems, Sara M
Winkler, Thomas W
Abecasis, Goncalo
Aben, Katja K
Alam, Dewan S
Alharthi, Sameer E
Allison, Matthew
Amouyel, Philippe
Asselbergs, Folkert W
Auer, Paul L
Balkau, Beverley
Bang, Lia E
Barroso, Ines
Bastarache, Lisa
Benn, Marianne
Bergmann, Sven
Bielak, Lawrence F
Blueher, Matthias
Boehnke, Michael
Boeing, Heiner
Boerwinkle, Eric
Boeger, 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 I
Chowdhury, Rajiv
Christensen, Cramer
Chu, Audrey Y
Cocca, Massimiliano
Collins, Francis S
Cook, James P
Corley, Janie
Galbany, Jordi Corominas
Cox, Amanda J
Crosslin, David S
Cuellar-Partida, Gabriel
D'Eustacchio, Angela
Danesh, John
Davies, Gail
Bakker, Paul IW
Groot, Mark CH
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
Franks, Paul W
Friedrich, Nele
Frikke-Schmidt, Ruth
Galesloot, Tessel E
Gan, Wei
Gandin, Ilaria
Gasparini, Paolo
Gibson, Jane
Giedraitis, Vilmantas
Gjesing, Anette P
Gordon-Larsen, Penny
Gorski, Mathias
Grabe, Hans-Joergen
Grant, Struan FA
Grarup, Niels
Griffiths, Helen L
Grove, Megan L
Gudnason, Vilmundur
Gustafsson, Stefan
Haessler, Jeff
Hakonarson, Hakon
Hammerschlag, Anke R
Hansen, Torben
Harris, Kathleen Mullan
Harris, Tamara B
Hattersley, Andrew T
Have, Christian T
Hayward, Caroline
He, Liang
Heard-Costa, Nancy L
Heath, Andrew C
Heid, Iris M
Helgeland, Oyvind
Hernesniemi, Jussi
Hewitt, Alex W
Holmen, Oddgeir L
Hovingh, G Kees
Howson, Joanna MM
Hu, Yao
Huang, Paul L
Huffman, Jennifer E
Ikram, M Arfan
Ingelsson, Erik
Jackson, Anne U
Jansson, Jan-Hakan
Jarvik, Gail P
Jensen, Gorm B
Jia, Yucheng
Johansson, Stefan
Jorgensen, Marit E
Jorgensen, Torben
Jukema, J Wouter
Kahali, Bratati
Kahn, Rene S
Kahonen, Mika
Kamstrup, Pia R
Kanoni, Stavroula
Kaprio, Jaakko
Karaleftheri, Maria
Kardia, Sharon LR
Karpe, Fredrik
Kathiresan, Sekar
Kee, Frank
Kiemeney, Lambertus A
Kim, Eric
Kitajima, Hidetoshi
Komulainen, Pirjo
Kooner, Jaspal S
Kooperberg, Charles
Korhonen, Tellervo
Kovacs, Peter
Kuivaniemi, Helena
Kutalik, Zoltan
Kuulasmaa, Kari
Kuusisto, Johanna
Laakso, Markku
Lakka, Timo A
Lamparter, David
Lange, Ethan M
Lange, Leslie A
Langenberg, Claudia
Larson, Eric B
Lee, Nanette R
Lehtimaki, Terho
Lewis, Cora E
Li, Huaixing
Li, Jin
Li-Gao, Ruifang
Lin, Honghuang
Lin, Keng-Hung
Lin, Li-An
Lin, Xu
Lind, Lars
Lindstrom, Jaana
Linneberg, Allan
Liu, Ching-Ti
Liu, Dajiang J
Liu, Yongmei
Lo, Ken S
Lophatananon, Artitaya
Lotery, Andrew J
Loukola, Anu
Luan, Jian'an
Lubitz, Steven A
Lyytikainen, Leo-Pekka
Mannisto, Satu
Marenne, Gaelle
Mazul, Angela L
McCarthy, Mark I
McKean-Cowdin, Roberta
Medland, Sarah E
Meidtner, Karina
Milani, Lili
Mistry, Vanisha
Mitchell, Paul
Mohlke, Karen L
Moilanen, Leena
Moitry, Marie
Montgomery, Grant W
Mook-Kanamori, Dennis O
Moore, Carmel
Mori, Trevor A
Morris, Andrew D
Morris, Andrew P
Mueller-Nurasyid, Martina
Munroe, Patricia B
Nalls, Mike A
Narisu, Narisu
Nelson, Christopher P
Neville, Matt
Nielsen, Sune F
Nikus, Kjell
Njolstad, Pal R
Nordestgaard, Borge G
Nyholt, Dale R
O'Connel, Jeffrey R
O'Donoghue, Michelle L
Loohuis, Loes M Olde
Ophoff, Roel A
Owen, Katharine R
Packard, Chris J
Padmanabhan, Sandosh
Palmer, Colin NA
Palmer, Nicholette D
Pasterkamp, Gerard
Patel, Aniruddh P
Pattie, Alison
Pedersen, Oluf
Peissig, Peggy L
Peloso, Gina M
Pennell, Craig E
Perola, Markus
Perry, James A
Perry, John RB
Pers, Tune H
Person, Thomas N
Peters, Annette
Petersen, Eva RB
Peyser, Patricia A
Pirie, Ailith
Polasek, Ozren
Polderman, Tinca J
Puolijoki, Hannu
Raitakari, Olli T
Rasheed, Asif
Rauramaa, Rainer
Reilly, Dermot F
Renstrom, Frida
Rheinberger, Myriam
Ridker, Paul M
Rioux, John D
Rivas, Manuel A
Roberts, David J
Robertson, Neil R
Robino, Antonietta
Rolandsson, Olov
Rudan, Igor
Ruth, Katherine S
Saleheen, Danish
Salomaa, Veikko
Samani, Nilesh J
Sapkota, Yadav
Sattar, Naveed
Schoen, Robert E
Schreiner, Pamela J
Schulze, Matthias B
Scott, Robert A
Segura-Lepe, Marcelo P
Shah, Svati H
Sheu, Wayne H-H
Sim, Xueling
Slater, Andrew J
Small, Kerrin S
Smith, Albert V
Southam, Lorraine
Spector, Timothy D
Speliotes, Elizabeth K
Starr, John M
Stefansson, Kari
Steinthorsdottir, Valgerdur
Stirrups, Kathleen E
Strauch, Konstantin
Stringham, Heather M
Stumvoll, Michael
Sun, Liang
Surendran, Praveen
Swift, Amy J
Tada, Hayato
Tansey, Katherine E
Tardif, Jean-Claude
Taylor, Kent D
Teumer, Alexander
Thompson, Deborah J
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Thuesen, Betina H
Toenjes, Anke
Tromp, Gerard
Trompet, Stella
Tsafantakis, Emmanouil
Tuomilehto, Jaakko
Tybjaerg-Hansen, Anne
Tyrer, Jonathan P
Uher, Rudolf
Uitterlinden, Andre G
Uusitupa, Matti
Laan, Sander W
Duijn, Cornelia M
Leeuwen, Nienke
van Setten, Jessica
Vanhala, Mauno
Varbo, Anette
Varga, Tibor V
Varma, Rohit
Edwards, Digna R Velez
Vermeulen, Sita H
Veronesi, Giovanni
Vestergaard, Henrik
Vitart, Veronique
Vogt, Thomas F
Voelker, Uwe
Vuckovic, Dragana
Wagenknecht, Lynne E
Walker, Mark
Wallentin, Lars
Wang, Feijie
Wang, Carol A
Wang, Shuai
Wang, Yiqin
Ware, Erin B
Wareham, Nicholas J
Warren, Helen R
Waterworth, Dawn M
Wessel, Jennifer
White, Harvey D
Willer, Cristen J
Wilson, James G
Witte, Daniel R
Wood, Andrew R
Wu, Ying
Yaghootkar, Hanieh
Yao, Jie
Yao, Pang
Yerges-Armstrong, Laura M
Young, Robin
Zeggini, Eleftheria
Zhan, Xiaowei
Zhang, Weihua
Zhao, Jing Hua
Zhao, Wei
Zhou, Wei
Zondervan, Krina T
Rotter, Jerome I
Pospisilik, John A
Rivadeneira, Fernando
Borecki, Ingrid B
Deloukas, Panos
Frayling, Timothy M
Lettre, Guillaume
North, Kari E
Lindgren, Cecilia M
Hirschhorn, Joel N
Loos, Ruth JF
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2018
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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.

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Nature Genetics

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50

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© 2018 Nature Publishing Group. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal website for access to the definitive, published version.

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Biological sciences

Biomedical and clinical sciences

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