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

  • Author(s): Turcot, Valérie
  • Lu, Yingchang
  • Highland, Heather M
  • Schurmann, Claudia
  • Justice, Anne E
  • Fine, Rebecca S
  • Bradfield, Jonathan P
  • Esko, Tõnu
  • 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, Gonçalo
  • 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, Inês
  • Bastarache, Lisa
  • Benn, Marianne
  • Bergmann, Sven
  • Bielak, Lawrence F
  • Blüher, Matthias
  • Boehnke, Michael
  • Boeing, Heiner
  • Boerwinkle, Eric
  • Böger, 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
  • Corominas Galbany, Jordi
  • Cox, Amanda J
  • Crosslin, David S
  • Cuellar-Partida, Gabriel
  • D'Eustacchio, Angela
  • Danesh, John
  • Davies, Gail
  • Bakker, Paul IW
  • Groot, Mark CH
  • Mutsert, Renée
  • Deary, Ian J
  • Dedoussis, George
  • Demerath, Ellen W
  • Heijer, Martin
  • Hollander, Anneke I
  • Ruijter, Hester M
  • Dennis, Joe G
  • Denny, Josh C
  • Di Angelantonio, Emanuele
  • Drenos, Fotios
  • Du, Mengmeng
  • Dubé, 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-Jörgen
  • 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, Øyvind
  • 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-Håkan
  • Jarvik, Gail P
  • Jensen, Gorm B
  • Jia, Yucheng
  • Johansson, Stefan
  • Jørgensen, Marit E
  • Jørgensen, Torben
  • Jukema, J Wouter
  • Kahali, Bratati
  • Kahn, René S
  • Kähönen, 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, Zoltán
  • 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
  • Lehtimäki, Terho
  • Lewis, Cora E
  • Li, Huaixing
  • Li, Jin
  • Li-Gao, Ruifang
  • Lin, Honghuang
  • Lin, Keng-Hung
  • Lin, Li-An
  • Lin, Xu
  • Lind, Lars
  • Lindström, 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
  • Lyytikäinen, Leo-Pekka
  • Männistö, Satu
  • Marenne, Gaëlle
  • 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
  • Müller-Nurasyid, Martina
  • Munroe, Patricia B
  • Nalls, Mike A
  • Narisu, Narisu
  • Nelson, Christopher P
  • Neville, Matt
  • Nielsen, Sune F
  • Nikus, Kjell
  • Njølstad, Pål R
  • Nordestgaard, Børge G
  • Nyholt, Dale R
  • O'Connel, Jeffrey R
  • O'Donoghue, Michelle L
  • Olde Loohuis, Loes M
  • 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
  • Renström, 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
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  • Sim, Xueling
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  • Smith, Albert V
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  • Strauch, Konstantin
  • Stringham, Heather M
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  • Surendran, Praveen
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  • Thorsteinsdottir, Unnur
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  • Tönjes, Anke
  • Tromp, Gerard
  • Trompet, Stella
  • Tsafantakis, Emmanouil
  • Tuomilehto, Jaakko
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  • Vestergaard, Henrik
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  • CHD Exome+ Consortium
  • EPIC-CVD Consortium
  • ExomeBP Consortium
  • Global Lipids Genetic Consortium
  • GoT2D Genes Consortium
  • EPIC InterAct Consortium
  • INTERVAL Study
  • ReproGen Consortium
  • T2D-Genes Consortium
  • MAGIC Investigators
  • Understanding Society Scientific Group
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Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951/
No data is associated with this publication.
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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