Genetic studies of body mass index yield new insights for obesity biology

Adam E Locke; Bratati Kahali; Sonja I Berndt; Anne E Justice; Tune H Pers; Felix R Day; Corey Powell; Sailaja Vedantam; Martin L Buchkovich; Jian Yang; Damien C Croteau-Chonka; Tonu Esko; Tove Fall; Teresa Ferreira; Stefan Gustafsson; Zoltán Kutalik; Jian'an Luan; Reedik Mägi; Joshua C Randall; Thomas W Winkler; Andrew R Wood; Tsegaselassie Workalemahu; Jessica D Faul; Jennifer A Smith; Jing Hua Zhao; Wei Zhao; Jin Chen; Rudolf Fehrmann; Åsa K Hedman; Juha Karjalainen; Ellen M Schmidt; Devin Absher; Najaf Amin; Denise Anderson; Marian Beekman; Jennifer L Bolton; Jennifer L Bragg-Gresham; Steven Buyske; Ayse Demirkan; Guohong Deng; Georg B Ehret; Bjarke Feenstra; Mary F Feitosa; Krista Fischer; Anuj Goel; Jian Gong; Anne U Jackson; Aaron Isaacs; Andrew Wong; Kevin B Jacobs; LifeLines Cohort Study; Joel N. Hirschorn; Ruth J. F. Loos; Elizabeth K. Speliotes

doi:10.1038/nature14177

Genetic studies of body mass index yield new insights for obesity biology

Adam E Locke, Bratati Kahali, Sonja I Berndt, Anne E Justice, Tune H Pers, Felix R Day, Corey Powell, Sailaja Vedantam, Martin L Buchkovich, Jian Yang, Damien C Croteau-Chonka, Tonu Esko, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Zoltán Kutalik, Jian'an Luan, Reedik Mägi, Joshua C Randall, Thomas W WinklerAndrew R Wood, Tsegaselassie Workalemahu, Jessica D Faul, Jennifer A Smith, Jing Hua Zhao, Wei Zhao, Jin Chen, Rudolf Fehrmann, Åsa K Hedman, Juha Karjalainen, Ellen M Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L Bolton, Jennifer L Bragg-Gresham, Steven Buyske, Ayse Demirkan, Guohong Deng, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Anuj Goel, Jian Gong, Anne U Jackson, Aaron Isaacs, Andrew Wong, Kevin B Jacobs, LifeLines Cohort Study, Joel N. Hirschorn^*, Ruth J. F. Loos^*, Elizabeth K. Speliotes^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Original language	English
Pages (from-to)	197-206
Number of pages	10
Journal	Nature
Volume	518
Issue number	7538
DOIs	https://doi.org/10.1038/nature14177
Publication status	Published - 12 Feb 2015
Externally published	Yes

Keywords

Adipogenesis/genetics
Adiposity/genetics
Age Factors
Body Mass Index
Continental Population Groups/genetics
Energy Metabolism/genetics
Europe/ethnology
Female
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study
Glutamic Acid/metabolism
Humans
Insulin/metabolism
Insulin Secretion
Male
Obesity/genetics
Polymorphism, Single Nucleotide/genetics
Quantitative Trait Loci/genetics
Synapses/metabolism

Access to Document

10.1038/nature14177

Cite this

Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R., Powell, C., Vedantam, S., Buchkovich, M. L., Yang, J., Croteau-Chonka, D. C., Esko, T., Fall, T., Ferreira, T., Gustafsson, S., Kutalik, Z., Luan, J., Mägi, R., Randall, J. C., ... Speliotes, E. K. (2015). Genetic studies of body mass index yield new insights for obesity biology. Nature, 518(7538), 197-206. https://doi.org/10.1038/nature14177

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title = "Genetic studies of body mass index yield new insights for obesity biology",

abstract = "Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. ",

keywords = "Adipogenesis/genetics, Adiposity/genetics, Age Factors, Body Mass Index, Continental Population Groups/genetics, Energy Metabolism/genetics, Europe/ethnology, Female, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Glutamic Acid/metabolism, Humans, Insulin/metabolism, Insulin Secretion, Male, Obesity/genetics, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Synapses/metabolism",

author = "Locke, {Adam E} and Bratati Kahali and Berndt, {Sonja I} and Justice, {Anne E} and Pers, {Tune H} and Day, {Felix R} and Corey Powell and Sailaja Vedantam and Buchkovich, {Martin L} and Jian Yang and Croteau-Chonka, {Damien C} and Tonu Esko and Tove Fall and Teresa Ferreira and Stefan Gustafsson and Zolt{\'a}n Kutalik and Jian'an Luan and Reedik M{\"a}gi and Randall, {Joshua C} and Winkler, {Thomas W} and Wood, {Andrew R} and Tsegaselassie Workalemahu and Faul, {Jessica D} and Smith, {Jennifer A} and Zhao, {Jing Hua} and Wei Zhao and Jin Chen and Rudolf Fehrmann and Hedman, {{\AA}sa K} and Juha Karjalainen and Schmidt, {Ellen M} and Devin Absher and Najaf Amin and Denise Anderson and Marian Beekman and Bolton, {Jennifer L} and Bragg-Gresham, {Jennifer L} and Steven Buyske and Ayse Demirkan and Guohong Deng and Ehret, {Georg B} and Bjarke Feenstra and Feitosa, {Mary F} and Krista Fischer and Anuj Goel and Jian Gong and Jackson, {Anne U} and Aaron Isaacs and Andrew Wong and Jacobs, {Kevin B} and {LifeLines Cohort Study} and Hirschorn, {Joel N.} and Loos, {Ruth J. F.} and Speliotes, {Elizabeth K.}",

year = "2015",

month = feb,

day = "12",

doi = "10.1038/nature14177",

language = "English",

volume = "518",

pages = "197--206",

journal = "Nature",

issn = "0028-0836",

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Locke, AE, Kahali, B, Berndt, SI, Justice, AE, Pers, TH, Day, FR, Powell, C, Vedantam, S, Buchkovich, ML, Yang, J, Croteau-Chonka, DC, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Mägi, R, Randall, JC, Winkler, TW, Wood, AR, Workalemahu, T, Faul, JD, Smith, JA, Zhao, JH, Zhao, W, Chen, J, Fehrmann, R, Hedman, ÅK, Karjalainen, J, Schmidt, EM, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, JL, Bragg-Gresham, JL, Buyske, S, Demirkan, A, Deng, G, Ehret, GB, Feenstra, B, Feitosa, MF, Fischer, K, Goel, A, Gong, J, Jackson, AU, Isaacs, A, Wong, A, Jacobs, KB, LifeLines Cohort Study, Hirschorn, JN, Loos, RJF & Speliotes, EK 2015, 'Genetic studies of body mass index yield new insights for obesity biology', Nature, vol. 518, no. 7538, pp. 197-206. https://doi.org/10.1038/nature14177

TY - JOUR

T1 - Genetic studies of body mass index yield new insights for obesity biology

AU - Locke, Adam E

AU - Kahali, Bratati

AU - Berndt, Sonja I

AU - Justice, Anne E

AU - Pers, Tune H

AU - Day, Felix R

AU - Powell, Corey

AU - Vedantam, Sailaja

AU - Buchkovich, Martin L

AU - Yang, Jian

AU - Croteau-Chonka, Damien C

AU - Esko, Tonu

AU - Fall, Tove

AU - Ferreira, Teresa

AU - Gustafsson, Stefan

AU - Kutalik, Zoltán

AU - Luan, Jian'an

AU - Mägi, Reedik

AU - Randall, Joshua C

AU - Winkler, Thomas W

AU - Wood, Andrew R

AU - Workalemahu, Tsegaselassie

AU - Faul, Jessica D

AU - Smith, Jennifer A

AU - Zhao, Jing Hua

AU - Zhao, Wei

AU - Chen, Jin

AU - Fehrmann, Rudolf

AU - Hedman, Åsa K

AU - Karjalainen, Juha

AU - Schmidt, Ellen M

AU - Absher, Devin

AU - Amin, Najaf

AU - Anderson, Denise

AU - Beekman, Marian

AU - Bolton, Jennifer L

AU - Bragg-Gresham, Jennifer L

AU - Buyske, Steven

AU - Demirkan, Ayse

AU - Deng, Guohong

AU - Ehret, Georg B

AU - Feenstra, Bjarke

AU - Feitosa, Mary F

AU - Fischer, Krista

AU - Goel, Anuj

AU - Gong, Jian

AU - Jackson, Anne U

AU - Isaacs, Aaron

AU - Wong, Andrew

AU - Jacobs, Kevin B

AU - LifeLines Cohort Study

AU - Hirschorn, Joel N.

AU - Loos, Ruth J. F.

AU - Speliotes, Elizabeth K.

PY - 2015/2/12

Y1 - 2015/2/12

N2 - Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

AB - Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

KW - Adipogenesis/genetics

KW - Adiposity/genetics

KW - Age Factors

KW - Body Mass Index

KW - Continental Population Groups/genetics

KW - Energy Metabolism/genetics

KW - Europe/ethnology

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Glutamic Acid/metabolism

KW - Humans

KW - Insulin/metabolism

KW - Insulin Secretion

KW - Male

KW - Obesity/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait Loci/genetics

KW - Synapses/metabolism

U2 - 10.1038/nature14177

DO - 10.1038/nature14177

M3 - Article

C2 - 25673413

SN - 0028-0836

VL - 518

SP - 197

EP - 206

JO - Nature

JF - Nature

IS - 7538

ER -