Article open access publication

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

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 50, 1, 2017

DOI:10.1038/s41588-017-0011-x, Dimensions: pub.1099876841, PMC: PMC5945951, PMID: 29273807,

Authors

Lu, Yingchang (3) (4) (5)
Fine, Rebecca S (8) (9) (10)
Esko, Tõnu (9) (10) (13)
Karaderi, Tugce (17) (18)
Locke, Adam Edward (20) (21)
Sivapalaratnam, Suthesh (23) (24) (25)
Manning, Alisa Knodle (8) (9) (24)
Reiner, Alex P (30) (31)
Vedantam, Sailaja L (8) (9) (10)
Aben, Katja K H (34) (35)
Alharthi, Sameer E (22) (37)
Amouyel, Philippe (39) (40) (41)
Barroso, Inês (16) (25) (48)
Benn, Marianne (49) (50)
Blüher, Matthias (53) (54)
Brandslund, Ivan (58) (59)
Chambers, John Campbell (67) (68) (69)
Chasman, Daniel Ian (8) (9) (70)
Chu, Audrey Y (71) (72)
Cox, Amanda Julie (29) (77)
Danesh, John Navid (16) (25)
Davies, Gail (74) (75)
Groot, Mark C H De (43) (80)
Deary, Ian John (74) (75)
Drenos, Fotios (44) (85)
Du, Mengmeng (31) (86)
Ferrannini, Ele (90) (91)
Florez, Jose C. (8) (9) (24)
Ford, Ian (93)
Franks, Paul William (8) (94) (95)
Gan, Wei (18)
Gasparini, Paolo P (63) (65)
Gorski, Mathias (33) (57)
Grabe, Hans Jörgen (96) (101)
Grant, Struan F A (12) (102)
Gudnason, Vilmundur G (103) (104)
Hakonarson, Hakon H (12) (102)
He, Liang (108) (109)
Heid, Iris M (33) (111)
Helgeland, Øyvind (112) (113)
Hewitt, Alex William (115) (116) (117) (118)
Hu, Yao (120)
Ingelsson, Erik (99) (121)
Jansson, Jan-Håkan (94) (122)
Johansson, Stefan E (112) (113)
Jørgensen, Torben Glarborg (50) (125) (126)
Kahali, Bratati (21) (127)
Kähönen, Mika A P (114) (128)
Kaprio, Jaakko A (108) (129) (130)
Karpe, Fredrik (132) (133)
Kathiresan, Sekar (8) (9) (24)
Kee, Frank (134)
Kim, Eric (14)
Komulainen, Pirjo (135) (136) (137)
Kooner, Jaspal Singh (67) (68) (69)
Korhonen, Tellervo (108) (129) (135)
Kovacs, Peter (53) (54)
Kutalik, Zoltán (51) (139)
Kuusisto, Johanna K (136) (140)
Laakso, Markku H (136) (140)
Lakka, Timo Antero (135) (136) (137)
Lamparter, David (51) (52)
Larson, Eric Berg (30) (141)
Li, Jin (121)
Lin, Xihong (120)
Lind, Lars (99)
Linneberg, Allan R (47) (50) (126)
Lo, Ken S (1) (2)
Loukola, Anu-Maria (108) (130)
Lubitz, Steven A (9) (24)
Mccarthy, Mark Ian (18) (132) (133)
Meidtner, Karina (55) (148)
Mistry, Vanisha (25) (48)
Mitchell, Paul (149) (150)
Moitry, Marie (151) (152)
Müller-Nurasyid, Martina (111) (153) (154) (155)
Nalls, Mike A (106) (156)
Neville, Matt J (132) (133)
Nyholt, Dale R (78) (157)
Ophoff, Roel A (43) (159)
Owen, Katharine R (132) (133)
Patel, Aniruddh Pradip (8) (9) (24)
Perola, Markus (13) (108) (129) (130)
Pers, Tune Hannes (50) (161)
Peters, Annette (148) (154) (162)
Polasek, Ozren (75) (163)
Rauramaa, Rainer (135) (137)
Renström, Frida (94) (95)
Ridker, Paul M (8) (70)
Rivas, Manuel A (9) (18)
Roberts, David J (25) (133) (168)
Robertson, Neil R (18) (133)
Saleheen, Danish (102) (167)
Sheu, Wayne Huey-Herng (144) (170) (171)
Sim, Xue Ling (21) (172)
Slater, Andrew J (173) (174)
Smith, Albert Vernon (103) (104)
Southam, Lorraine (16) (18)
Stefansson, Kari (104) (175)
Strauch, Konstantin (111) (155)
Sun, Liang (108) (109)
Tada, Hayato (8) (176)
Tansey, Katherine E (85) (177)
Tromp, Gerard C (66) (138)
Tuomilehto, Jaakko (37) (129) (179) (180)
Uher, Rudolf (181)
Leeuwen, Nienke (81) (84)
Vanhala, Mauno J (136) (182)
Varbo, Anette (49) (50)
Varma, Rohit (147)
Vestergaard, Henrik (50) (124)
Völker, Uwe (96) (154)
Vuckovic, Dragana (63) (65)
Walker, Mark (184)
Wang, Feijie (120)
Wang, Shuai (110)
Wang, Yiqin (120)
Witte, Daniel Rinse (188) (189)
Wu, Ying (100)
Yao, Jie (14)
Yao, Pang (120)
Young, Robin David (25) (93)
Zhang, Weihua (67) (69)
Zhao, Wei (102)
Zhao, Wei (21)
Zhou, Wei (21)
Deloukas, Panos G (22) (37)
Hirschhorn, Joel N * (8) (9) (10)

* Corresponding author

Affiliations

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  2. (2) University of Montreal, grid.14848.31
  3. (3) Vanderbilt University Medical Center, grid.412807.8
  4. (4) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  5. (5) Vanderbilt University, grid.152326.1
  6. (6) The University of Texas Health Science Center at Houston, grid.267308.8
  7. (7) University of North Carolina System, grid.410711.2
  8. (8) Harvard University, grid.38142.3c
  9. (9) Broad Institute, grid.66859.34
  10. (10) Boston Children's Hospital, grid.2515.3
  11. (11) Quantinuum Research, LLC, San Diego, CA, USA
  12. (12) Children's Hospital of Philadelphia, grid.239552.a
  13. (13) University of Tartu, grid.10939.32
  14. (14) Harbor–UCLA Medical Center, grid.239844.0
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  16. (16) Wellcome Sanger Institute, grid.10306.34
  17. (17) Eastern Mediterranean University, grid.461270.6
  18. (18) Wellcome Centre for Human Genetics, grid.270683.8
  19. (19) Max Planck Institute of Immunobiology and Epigenetics, grid.429509.3
  20. (20) Washington University in St. Louis, grid.4367.6
  21. (21) University of Michigan, grid.214458.e
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  32. (32) Institute of Metabolic Science, grid.470900.a
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  49. (49) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
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  51. (51) Swiss Institute of Bioinformatics, grid.419765.8
  52. (52) University of Lausanne, grid.9851.5
  53. (53) IFB Adiposity Diseases, grid.483476.a
  54. (54) Leipzig University, grid.9647.c
  55. (55) German Institute of Human Nutrition, grid.418213.d
  56. (56) Baylor College of Medicine, grid.39382.33
  57. (57) University Hospital Regensburg, grid.411941.8
  58. (58) University of Southern Denmark, grid.10825.3e, SDU
  59. (59) Sygehus Lillebælt, grid.459623.f, Southern Denmark Region
  60. (60) NIHR Maudsley Dementia Biomedical Research Unit, grid.454378.9
  61. (61) King's College London, grid.13097.3c
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  92. (92) Federal University of Toulouse Midi-Pyrénées, grid.508721.9
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  101. (101) German Center for Neurodegenerative Diseases, grid.424247.3
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  190. (190) The University of Texas Southwestern Medical Center, grid.267313.2
  191. (191) Department of Epidemiology and Carolina Center of Genome Sciences, Chapel Hill, NC, USA

Description

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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2018: Realized

Research area: Medicine

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2018: Level 3

Research area: Medicine

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Times Cited: 144

Field Citation Ratio (FCR): 25.62

Relative Citation ratio (RCR): 10.36

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Green, Published