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

Turcot, V and Lu, Y and Highland, HM and Schurmann, C and Justice, AE and Fine, RS and Bradfield, JP and Esko, T and Giri, A and Graff, M and Guo, X and Hendricks, AE and Karaderi, T and Lempradl, A and Locke, AE and Mahajan, A and Marouli, E and Sivapalaratnam, S and Young, KL and Alfred, T and Feitosa, MF and Masca, NGD and Manning, AK and Medina-Gomez, C and Mudgal, P and Ng, MCY and Reiner, AP and Vedantam, S and Willems, SM and Winkler, TW and Abecasis, G and Aben, KK and Alam, DS and Alharthi, SE and Allison, M and Amouyel, P and Asselbergs, FW and Auer, PL and Balkau, B and Bang, LE and Barroso, I and Bastarache, L and Benn, M and Bergmann, S and Bielak, LF and Blüher, M and Boehnke, M and Boeing, H and Boerwinkle, E and Böger, CA and Bork-Jensen, J and Bots, ML and Bottinger, EP and Bowden, DW and Brandslund, I and Breen, G and Brilliant, MH and Broer, L and Brumat, M and Burt, AA and Butterworth, AS and Campbell, PT and Cappellani, S and Carey, DJ and Catamo, E and Caulfield, MJ and Chambers, JC and Chasman, DI and Chen, Y-DI and Chowdhury, R and Christensen, C and Chu, AY and Cocca, M and Cook, JP and Corley, J and Corominas Galbany, J and Cox, AJ and Crosslin, DS and Cuellar-Partida, G and D'Eustacchio, A and Danesh, J and Davies, G and Bakker, PIW and Groot, MCH and Mutsert, R and Deary, IJ and Dedoussis, G and Demerath, EW and Heijer, M and Hollander, AI and Ruijter, HM and Dennis, JG and Denny, JC and Angelantonio, E and Drenos, F and Du, M and Dubé, M-P and Dunning, AM and Easton, DF and Edwards, TL and Ellinghaus, D and Ellinor, PT and Elliott, P and Evangelou, E and Farmaki, A-E and Farooqi, IS and Faul, JD and Fauser, S and Feng, S and Ferrannini, E and Ferrieres, J and Florez, JC and Ford, I and Fornage, M and Franco, OH and Franke, A and Franks, PW and Friedrich, N and Frikke-Schmidt, R and Galesloot, TE and Gan, W and Gandin, I and Gasparini, P and Gibson, J and Giedraitis, V and Gjesing, AP and Gordon-Larsen, P and Gorski, M and Grabe, H-J and Grant, SFA and Grarup, N and Griffiths, HL and Grove, ML and Gudnason, V and Gustafsson, S and Haessler, J and Hakonarson, H and Hammerschlag, AR and Hansen, T and Harris, KM and Harris, TB and Hattersley, AT and Have, CT and Hayward, C and He, L and Heard-Costa, NL and Heath, AC and Heid, IM and Helgeland, � and Hernesniemi, J and Hewitt, AW and Holmen, OL and Hovingh, GK and Howson, JMM and Hu, Y and Huang, PL and Huffman, JE and Ikram, MA and Ingelsson, E and Jackson, AU and Jansson, J-H and Jarvik, GP and Jensen, GB and Jia, Y and Johansson, S and Jørgensen, ME and Jørgensen, T and Jukema, JW and Kahali, B and Kahn, RS and Kähönen, M and Kamstrup, PR and Kanoni, S and Kaprio, J and Karaleftheri, M and Kardia, SLR and Karpe, F and Kathiresan, S and Kee, F and Kiemeney, LA and Kim, E and Kitajima, H and Komulainen, P and Kooner, JS and Kooperberg, C and Korhonen, T and Kovacs, P and Kuivaniemi, H and Kutalik, Z and Kuulasmaa, K and Kuusisto, J and Laakso, M and Lakka, TA and Lamparter, D and Lange, EM and Lange, LA and Langenberg, C and Larson, EB and Lee, NR and Lehtimäki, T and Lewis, CE and Li, H and Li, J and Li-Gao, R and Lin, H and Lin, K-H and Lin, L-A and Lin, X and Lind, L and Lindström, J and Linneberg, A and Liu, C-T and Liu, DJ and Liu, Y and Lo, KS and Lophatananon, A and Lotery, AJ and Loukola, A and Luan, J and Lubitz, SA and Lyytikäinen, L-P and Männistö, S and Marenne, G and Mazul, AL and McCarthy, MI and McKean-Cowdin, R and Medland, SE and Meidtner, K and Milani, L and Mistry, V and Mitchell, P and Mohlke, KL and Moilanen, L and Moitry, M and Montgomery, GW and Mook-Kanamori, DO and Moore, C and Mori, TA and Morris, AD and Morris, AP and Müller-Nurasyid, M and Munroe, PB and Nalls, MA and Narisu, N and Nelson, CP and Neville, M and Nielsen, SF and Nikus, K and Njølstad, PR and Nordestgaard, BøG and Nyholt, DR and O'Connel, JR and O'Donoghue, ML and Olde Loohuis, LM and Ophoff, RA and Owen, KR and Packard, CJ and Padmanabhan, S and Palmer, CNA and Palmer, ND and Pasterkamp, G and Patel, AP and Pattie, A and Pedersen, O and Peissig, PL and Peloso, GM and Pennell, CE and Perola, M and Perry, JA and Perry, JRB and Pers, TH and Person, TN and Peters, A and Petersen, ERB and Peyser, PA and Pirie, A and Polasek, O and Polderman, TJ and Puolijoki, H and Raitakari, OT and Rasheed, A and Rauramaa, R and Reilly, DF and Renström, F and Rheinberger, M and Ridker, PM and Rioux, JD and Rivas, MA and Roberts, DJ and Robertson, NR and Robino, A and Rolandsson, O and Rudan, I and Ruth, KS and Saleheen, D and Salomaa, V and Samani, NJ and Sapkota, Y and Sattar, N and Schoen, RE and Schreiner, PJ and Schulze, MB and Scott, RA and Segura-Lepe, MP and Shah, SH and Sheu, WH-H and Sim, X and Slater, AJ and Small, KS and Smith, AV and Southam, L and Spector, TD and Speliotes, EK and Starr, JM and Stefansson, K and Steinthorsdottir, V and Stirrups, KE and Strauch, K and Stringham, HM and Stumvoll, M and Sun, L and Surendran, P and Swift, AJ and Tada, H and Tansey, KE and Tardif, J-C and Taylor, KD and Teumer, A and Thompson, DJ and Thorleifsson, G and Thorsteinsdottir, U and Thuesen, BH and Tönjes, A and Tromp, G and Trompet, S and Tsafantakis, E and Tuomilehto, J and Tybjaerg-Hansen, A and Tyrer, JP and Uher, R and Uitterlinden, AG and Uusitupa, M and Laan, SW and Duijn, CM and Leeuwen, N and Van Setten, J and Vanhala, M and Varbo, A and Varga, TV and Varma, R and Velez Edwards, DR and Vermeulen, SH and Veronesi, G and Vestergaard, H and Vitart, V and Vogt, TF and Völker, U and Vuckovic, D and Wagenknecht, LE and Walker, M and Wallentin, L and Wang, F and Wang, CA and Wang, S and Wang, Y and Ware, EB and Wareham, NJ and Warren, HR and Waterworth, DM and Wessel, J and White, HD and Willer, CJ and Wilson, JG and Witte, DR and Wood, AR and Wu, Y and Yaghootkar, H and Yao, J and Yao, P and Yerges-Armstrong, LM and Young, R and Zeggini, E and Zhan, X and Zhang, W and Zhao, JH and Zhao, W and Zhou, W and Zondervan, KT and 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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Official URL: https://doi.org/10.1038/s41588-017-0011-x


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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