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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.

SUBMITTER: Locke AE

PROVIDER: S-EPMC4382211 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Locke Adam E AE Kahali Bratati B Berndt Sonja I SI Justice Anne E AE Pers Tune H TH Day Felix R FR Powell Corey C Vedantam Sailaja S Buchkovich Martin L ML Yang Jian J Croteau-Chonka Damien C DC Esko Tonu T Fall Tove T Ferreira Teresa T Gustafsson Stefan S Kutalik Zoltán Z Luan Jian'an J Mägi Reedik R Randall Joshua C JC Winkler Thomas W TW Wood Andrew R AR Workalemahu Tsegaselassie T Faul Jessica D JD Smith Jennifer A JA Zhao Jing Hua JH Zhao Wei W Chen Jin J Fehrmann Rudolf R Hedman Åsa K ÅK Karjalainen Juha J Schmidt Ellen M EM Absher Devin D Amin Najaf N Anderson Denise D Beekman Marian M Bolton Jennifer L JL Bragg-Gresham Jennifer L JL Buyske Steven S Demirkan Ayse A Deng Guohong G Ehret Georg B GB Feenstra Bjarke B Feitosa Mary F MF Fischer Krista K Goel Anuj A Gong Jian J Jackson Anne U AU Kanoni Stavroula S Kleber Marcus E ME Kristiansson Kati K Lim Unhee U Lotay Vaneet V Mangino Massimo M Leach Irene Mateo IM Medina-Gomez Carolina C Medland Sarah E SE Nalls Michael A MA Palmer Cameron D CD Pasko Dorota D Pechlivanis Sonali S Peters Marjolein J MJ Prokopenko Inga I Shungin Dmitry D Stančáková Alena A Strawbridge Rona J RJ Sung Yun Ju YJ Tanaka Toshiko T Teumer Alexander A Trompet Stella S van der Laan Sander W SW van Setten Jessica J Van Vliet-Ostaptchouk Jana V JV Wang Zhaoming Z Yengo Loïc L Zhang Weihua W Isaacs Aaron A Albrecht Eva E Ärnlöv Johan J Arscott Gillian M GM Attwood Antony P AP Bandinelli Stefania S Barrett Amy A Bas Isabelita N IN Bellis Claire C Bennett Amanda J AJ Berne Christian C Blagieva Roza R Blüher Matthias M Böhringer Stefan S Bonnycastle Lori L LL Böttcher Yvonne Y Boyd Heather A HA Bruinenberg Marcel M Caspersen Ida H IH Chen Yii-Der Ida YI Clarke Robert R Daw E Warwick EW de Craen Anton J M AJM Delgado Graciela G Dimitriou Maria M Doney Alex S F ASF Eklund Niina N Estrada Karol K Eury Elodie E Folkersen Lasse L Fraser Ross M RM Garcia Melissa E ME Geller Frank F Giedraitis Vilmantas V Gigante Bruna B Go Alan S AS Golay Alain A Goodall Alison H AH Gordon Scott D SD Gorski Mathias M Grabe Hans-Jörgen HJ Grallert Harald H Grammer Tanja B TB Gräßler Jürgen J Grönberg Henrik H Groves Christopher J CJ Gusto Gaëlle G Haessler Jeffrey J Hall Per P Haller Toomas T Hallmans Goran G Hartman Catharina A CA Hassinen Maija M Hayward Caroline C Heard-Costa Nancy L NL Helmer Quinta Q Hengstenberg Christian C Holmen Oddgeir O Hottenga Jouke-Jan JJ James Alan L AL Jeff Janina M JM Johansson Åsa Å Jolley Jennifer J Juliusdottir Thorhildur T Kinnunen Leena L Koenig Wolfgang W Koskenvuo Markku M Kratzer Wolfgang W Laitinen Jaana J Lamina Claudia C Leander Karin K Lee Nanette R NR Lichtner Peter P Lind Lars L Lindström Jaana J Lo Ken Sin KS Lobbens Stéphane S Lorbeer Roberto R Lu Yingchang Y Mach François F Magnusson Patrik K E PKE Mahajan Anubha A McArdle Wendy L WL McLachlan Stela S Menni Cristina C Merger Sigrun S Mihailov Evelin E Milani Lili L Moayyeri Alireza A Monda Keri L KL Morken Mario A MA Mulas Antonella A Müller Gabriele G Müller-Nurasyid Martina M Musk Arthur W AW Nagaraja Ramaiah R Nöthen Markus M MM Nolte Ilja M IM Pilz Stefan S Rayner Nigel W NW Renstrom Frida F Rettig Rainer R Ried Janina S JS Ripke Stephan S Robertson Neil R NR Rose Lynda M LM Sanna Serena S Scharnagl Hubert H Scholtens Salome S Schumacher Fredrick R FR Scott William R WR Seufferlein Thomas T Shi Jianxin J Smith Albert Vernon AV Smolonska Joanna J Stanton Alice V AV Steinthorsdottir Valgerdur V Stirrups Kathleen K Stringham Heather M HM Sundström Johan J Swertz Morris A MA Swift Amy J AJ Syvänen Ann-Christine AC Tan Sian-Tsung ST Tayo Bamidele O BO Thorand Barbara B Thorleifsson Gudmar G Tyrer Jonathan P JP Uh Hae-Won HW Vandenput Liesbeth L Verhulst Frank C FC Vermeulen Sita H SH Verweij Niek N Vonk Judith M JM Waite Lindsay L LL Warren Helen R HR Waterworth Dawn D Weedon Michael N MN Wilkens Lynne R LR Willenborg Christina C Wilsgaard Tom T Wojczynski Mary K MK Wong Andrew A Wright Alan F AF Zhang Qunyuan Q Brennan Eoin P EP Choi Murim M Dastani Zari Z Drong Alexander W AW Eriksson Per P Franco-Cereceda Anders A Gådin Jesper R JR Gharavi Ali G AG Goddard Michael E ME Handsaker Robert E RE Huang Jinyan J Karpe Fredrik F Kathiresan Sekar S Keildson Sarah S Kiryluk Krzysztof K Kubo Michiaki M Lee Jong-Young JY Liang Liming L Lifton Richard P RP Ma Baoshan B McCarroll Steven A SA McKnight Amy J AJ Min Josine L JL Moffatt Miriam F MF Montgomery Grant W GW Murabito Joanne M JM Nicholson George G Nyholt Dale R DR Okada Yukinori Y Perry John R B JRB Dorajoo Rajkumar R Reinmaa Eva E Salem Rany M RM Sandholm Niina N Scott Robert A RA Stolk Lisette L Takahashi Atsushi A Tanaka Toshihiro T van 't Hooft Ferdinand M FM Vinkhuyzen Anna A E AAE Westra Harm-Jan HJ Zheng Wei W Zondervan Krina T KT Heath Andrew C AC Arveiler Dominique D Bakker Stephan J L SJL Beilby John J Bergman Richard N RN Blangero John J Bovet Pascal P Campbell Harry H Caulfield Mark J MJ Cesana Giancarlo G Chakravarti Aravinda A Chasman Daniel I DI Chines Peter S PS Collins Francis S FS Crawford Dana C DC Cupples L Adrienne LA Cusi Daniele D Danesh John J de Faire Ulf U den Ruijter Hester M HM Dominiczak Anna F AF Erbel Raimund R Erdmann Jeanette J Eriksson Johan G JG Farrall Martin M Felix Stephan B SB Ferrannini Ele E Ferrières Jean J Ford Ian I Forouhi Nita G NG Forrester Terrence T Franco Oscar H OH Gansevoort Ron T RT Gejman Pablo V PV Gieger Christian C Gottesman Omri O Gudnason Vilmundur V Gyllensten Ulf U Hall Alistair S AS Harris Tamara B TB Hattersley Andrew T AT Hicks Andrew A AA Hindorff Lucia A LA Hingorani Aroon D AD Hofman Albert A Homuth Georg G Hovingh G Kees GK Humphries Steve E SE Hunt Steven C SC Hyppönen Elina E Illig Thomas T Jacobs Kevin B KB Jarvelin Marjo-Riitta MR Jöckel Karl-Heinz KH Johansen Berit B Jousilahti Pekka P Jukema J Wouter JW Jula Antti M AM Kaprio Jaakko J Kastelein John J P JJP Keinanen-Kiukaanniemi Sirkka M SM Kiemeney Lambertus A LA Knekt Paul P Kooner Jaspal S JS Kooperberg Charles C Kovacs Peter P Kraja Aldi T AT Kumari Meena M Kuusisto Johanna J Lakka Timo A TA Langenberg Claudia C Marchand Loic Le LL Lehtimäki Terho T Lyssenko Valeriya V Männistö Satu S Marette André A Matise Tara C TC McKenzie Colin A CA McKnight Barbara B Moll Frans L FL Morris Andrew D AD Morris Andrew P AP Murray Jeffrey C JC Nelis Mari M Ohlsson Claes C Oldehinkel Albertine J AJ Ong Ken K KK Madden Pamela A F PAF Pasterkamp Gerard G Peden John F JF Peters Annette A Postma Dirkje S DS Pramstaller Peter P PP Price Jackie F JF Qi Lu L Raitakari Olli T OT Rankinen Tuomo T Rao D C DC Rice Treva K TK Ridker Paul M PM Rioux John D JD Ritchie Marylyn D MD Rudan Igor I Salomaa Veikko V Samani Nilesh J NJ Saramies Jouko J Sarzynski Mark A MA Schunkert Heribert H Schwarz Peter E H PEH Sever Peter P Shuldiner Alan R AR Sinisalo Juha J Stolk Ronald P RP Strauch Konstantin K Tönjes Anke A Trégouët David-Alexandre DA Tremblay Angelo A Tremoli Elena E Virtamo Jarmo J Vohl Marie-Claude MC Völker Uwe U Waeber Gérard G Willemsen Gonneke G Witteman Jacqueline C JC Zillikens M Carola MC Adair Linda S LS Amouyel Philippe P Asselbergs Folkert W FW Assimes Themistocles L TL Bochud Murielle M Boehm Bernhard O BO Boerwinkle Eric E Bornstein Stefan R SR Bottinger Erwin P EP Bouchard Claude C Cauchi Stéphane S Chambers John C JC Chanock Stephen J SJ Cooper Richard S RS de Bakker Paul I W PIW Dedoussis George G Ferrucci Luigi L Franks Paul W PW Froguel Philippe P Groop Leif C LC Haiman Christopher A CA Hamsten Anders A Hui Jennie J Hunter David J DJ Hveem Kristian K Kaplan Robert C RC Kivimaki Mika M Kuh Diana D Laakso Markku M Liu Yongmei Y Martin Nicholas G NG März Winfried W Melbye Mads M Metspalu Andres A Moebus Susanne S Munroe Patricia B PB Njølstad Inger I Oostra Ben A BA Palmer Colin N A CNA Pedersen Nancy L NL Perola Markus M Pérusse Louis L Peters Ulrike U Power Chris C Quertermous Thomas T Rauramaa Rainer R Rivadeneira Fernando F Saaristo Timo E TE Saleheen Danish D Sattar Naveed N Schadt Eric E EE Schlessinger David D Slagboom P Eline PE Snieder Harold H Spector Tim D TD Thorsteinsdottir Unnur U Stumvoll Michael M Tuomilehto Jaakko J Uitterlinden André G AG Uusitupa Matti M van der Harst Pim P Walker Mark M Wallaschofski Henri H Wareham Nicholas J NJ Watkins Hugh H Weir David R DR Wichmann H-Erich HE Wilson James F JF Zanen Pieter P Borecki Ingrid B IB Deloukas Panos P Fox Caroline S CS Heid Iris M IM O'Connell Jeffrey R JR Strachan David P DP Stefansson Kari K van Duijn Cornelia M CM Abecasis Gonçalo R GR Franke Lude L Frayling Timothy M TM McCarthy Mark I MI Visscher Peter M PM Scherag André A Willer Cristen J CJ Boehnke Michael M Mohlke Karen L KL Lindgren Cecilia M CM Beckmann Jacques S JS Barroso Inês I North Kari E KE Ingelsson Erik E Hirschhorn Joel N JN Loos Ruth J F RJF Speliotes Elizabeth K EK

Nature 20150201 7538

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 signific ...[more]

PMID: 25673413

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Project description:BackgroundAccurate obesity classification is important so that appropriate intervention can be instituted to modify metabolic risk factors. Commonly utilized body mass index (BMI) and percentage body fat (PBF) are influenced by lean mass whereas fat mass index (FMI) measures only body fat. This study compares the prevalence of obesity and metabolic risk factors with FMI, BMI and PBF using DXA (dual-energy x-ray absorptiometry).Methods489 women randomly recruited from the electoral roll were stratified into 4 age groups; 40-49, 50-59, 60-69 and 70-79 years from 2000 to 2001. Clinical data and DXA body composition were obtained. Statistical analyses were performed using Medcalc v15 (Ostend, Belgium) with significance level at p = 0.05 (two-tailed).ResultsThere was higher prevalence of obesity using PBF compared to BMI and FMI (p<0.001). This difference was greater from age 50-59 (p<0.05) which may be explained by age-related lean mass loss. PBF over-classified obesity in over 35% of normal and 95% of overweight categories compared to FMI and BMI. BMI has a sensitivity of 78.9% and specificity of 98.3% for obesity using FMI as the standard. BMI under-classified obesity in the overweight category by 14.9% compared to FMI. There was no difference in diabetes, dyslipidemia, hypertension and metabolic syndrome prevalence within the BMI-obesity and FMI-obesity categories (p>0.05).ConclusionPBF classified more obesity than BMI and FMI because of its low pre-determined threshold. The greater difference with PBF compared to BMI and FMI from the 50-59 decade onwards can be attributed to age-related lean mass loss. BMI had the lowest sensitivity for obesity diagnosis. BMI under-classified obesity in the overweight category compared to FMI due to its inability to differentiate lean mass. However, there was no significant difference in the prevalence of metabolic risk factors between BMI and FMI-obesity categories indicating that fat location may influence metabolic dysregulation.

Project description:BACKGROUND:Obesity, typically quantified in terms of Body Mass Index (BMI) exceeding threshold values, is considered a leading cause of premature death worldwide. For given body size (BMI), it is recognized that risk is also affected by body shape, particularly as a marker of abdominal fat deposits. Waist circumference (WC) is used as a risk indicator supplementary to BMI, but the high correlation of WC with BMI makes it hard to isolate the added value of WC. METHODS AND FINDINGS:We considered a USA population sample of 14,105 non-pregnant adults (age ? 18) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 with follow-up for mortality averaging 5 yr (828 deaths). We developed A Body Shape Index (ABSI) based on WC adjusted for height and weight: ABSI ? WC/(BMI(2/3)height(1/2)). ABSI had little correlation with height, weight, or BMI. Death rates increased approximately exponentially with above average baseline ABSI (overall regression coefficient of +33% per standard deviation of ABSI [95% confidence interval: +20%-+48%), whereas elevated death rates were found for both high and low values of BMI and WC. 22% (8%-41%) of the population mortality hazard was attributable to high ABSI, compared to 15% (3%-30%) for BMI and 15% (4%-29%) for WC. The association of death rate with ABSI held even when adjusted for other known risk factors including smoking, diabetes, blood pressure, and serum cholesterol. ABSI correlation with mortality hazard held across the range of age, sex, and BMI, and for both white and black ethnicities (but not for Mexican ethnicity), and was not weakened by excluding deaths from the first 3 yr of follow-up. CONCLUSIONS:Body shape, as measured by ABSI, appears to be a substantial risk factor for premature mortality in the general population derivable from basic clinical measurements. ABSI expresses the excess risk from high WC in a convenient form that is complementary to BMI and to other known risk factors.

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

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

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