Dataset Information

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

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.

SUBMITTER: Turcot V

PROVIDER: S-EPMC5945951 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Turcot Valérie V Lu Yingchang Y Highland Heather M HM Schurmann Claudia C Justice Anne E AE Fine Rebecca S RS Bradfield Jonathan P JP Esko Tõnu T Giri Ayush A Graff Mariaelisa M Guo Xiuqing X Hendricks Audrey E AE Karaderi Tugce T Lempradl Adelheid A Locke Adam E AE Mahajan Anubha A Marouli Eirini E Sivapalaratnam Suthesh S Young Kristin L KL Alfred Tamuno T Feitosa Mary F MF Masca Nicholas G D NGD Manning Alisa K AK Medina-Gomez Carolina C Mudgal Poorva P Ng Maggie C Y MCY Reiner Alex P AP Vedantam Sailaja S Willems Sara M SM Winkler Thomas W TW Abecasis Gonçalo G Aben Katja K KK Alam Dewan S DS Alharthi Sameer E SE Allison Matthew M Amouyel Philippe P Asselbergs Folkert W FW Auer Paul L PL Balkau Beverley B Bang Lia E LE Barroso Inês I Bastarache Lisa L Benn Marianne M Bergmann Sven S Bielak Lawrence F LF Blüher Matthias M Boehnke Michael M Boeing Heiner H Boerwinkle Eric E Böger Carsten A CA Bork-Jensen Jette J Bots Michiel L ML Bottinger Erwin P EP Bowden Donald W DW Brandslund Ivan I Breen Gerome G Brilliant Murray H MH Broer Linda L Brumat Marco M Burt Amber A AA Butterworth Adam S AS Campbell Peter T PT Cappellani Stefania S Carey David J DJ Catamo Eulalia E Caulfield Mark J MJ Chambers John C JC Chasman Daniel I DI Chen Yii-Der I YI Chowdhury Rajiv R Christensen Cramer C Chu Audrey Y AY Cocca Massimiliano M Collins Francis S FS Cook James P JP Corley Janie J Corominas Galbany Jordi J Cox Amanda J AJ Crosslin David S DS Cuellar-Partida Gabriel G D'Eustacchio Angela A Danesh John J Davies Gail G Bakker Paul I W PIW Groot Mark C H MCH Mutsert Renée R Deary Ian J IJ Dedoussis George G Demerath Ellen W EW Heijer Martin M Hollander Anneke I AI Ruijter Hester M HM Dennis Joe G JG Denny Josh C JC Di Angelantonio Emanuele E Drenos Fotios F Du Mengmeng M Dubé Marie-Pierre MP Dunning Alison M AM Easton Douglas F DF Edwards Todd L TL Ellinghaus David D Ellinor Patrick T PT Elliott Paul P Evangelou Evangelos E Farmaki Aliki-Eleni AE Farooqi I Sadaf IS Faul Jessica D JD Fauser Sascha S Feng Shuang S Ferrannini Ele E Ferrieres Jean J Florez Jose C JC Ford Ian I Fornage Myriam M Franco Oscar H OH Franke Andre A Franks Paul W PW Friedrich Nele N Frikke-Schmidt Ruth R Galesloot Tessel E TE Gan Wei W Gandin Ilaria I Gasparini Paolo P Gibson Jane J Giedraitis Vilmantas V Gjesing Anette P AP Gordon-Larsen Penny P Gorski Mathias M Grabe Hans-Jörgen HJ Grant Struan F A SFA Grarup Niels N Griffiths Helen L HL Grove Megan L ML Gudnason Vilmundur V Gustafsson Stefan S Haessler Jeff J Hakonarson Hakon H Hammerschlag Anke R AR Hansen Torben T Harris Kathleen Mullan KM Harris Tamara B TB Hattersley Andrew T AT Have Christian T CT Hayward Caroline C He Liang L Heard-Costa Nancy L NL Heath Andrew C AC Heid Iris M IM Helgeland Øyvind Ø Hernesniemi Jussi J Hewitt Alex W AW Holmen Oddgeir L OL Hovingh G Kees GK Howson Joanna M M JMM Hu Yao Y Huang Paul L PL Huffman Jennifer E JE Ikram M Arfan MA Ingelsson Erik E Jackson Anne U AU Jansson Jan-Håkan JH Jarvik Gail P GP Jensen Gorm B GB Jia Yucheng Y Johansson Stefan S Jørgensen Marit E ME Jørgensen Torben T Jukema J Wouter JW Kahali Bratati B Kahn René S RS Kähönen Mika M Kamstrup Pia R PR Kanoni Stavroula S Kaprio Jaakko J Karaleftheri Maria M Kardia Sharon L R SLR Karpe Fredrik F Kathiresan Sekar S Kee Frank F Kiemeney Lambertus A LA Kim Eric E Kitajima Hidetoshi H Komulainen Pirjo P Kooner Jaspal S JS Kooperberg Charles C Korhonen Tellervo T Kovacs Peter P Kuivaniemi Helena H Kutalik Zoltán Z Kuulasmaa Kari K Kuusisto Johanna J Laakso Markku M Lakka Timo A TA Lamparter David D Lange Ethan M EM Lange Leslie A LA Langenberg Claudia C Larson Eric B EB Lee Nanette R NR Lehtimäki Terho T Lewis Cora E CE Li Huaixing H Li Jin J Li-Gao Ruifang R Lin Honghuang H Lin Keng-Hung KH Lin Li-An LA Lin Xu X Lind Lars L Lindström Jaana J Linneberg Allan A Liu Ching-Ti CT Liu Dajiang J DJ Liu Yongmei Y Lo Ken S KS Lophatananon Artitaya A Lotery Andrew J AJ Loukola Anu A Luan Jian'an J Lubitz Steven A SA Lyytikäinen Leo-Pekka LP Männistö Satu S Marenne Gaëlle G Mazul Angela L AL McCarthy Mark I MI McKean-Cowdin Roberta R Medland Sarah E SE Meidtner Karina K Milani Lili L Mistry Vanisha V Mitchell Paul P Mohlke Karen L KL Moilanen Leena L Moitry Marie M Montgomery Grant W GW Mook-Kanamori Dennis O DO Moore Carmel C Mori Trevor A TA Morris Andrew D AD Morris Andrew P AP Müller-Nurasyid Martina M Munroe Patricia B PB Nalls Mike A MA Narisu Narisu N Nelson Christopher P CP Neville Matt M Nielsen Sune F SF Nikus Kjell K Njølstad Pål R PR Nordestgaard Børge G BG Nyholt Dale R DR O'Connel Jeffrey R JR O'Donoghue Michelle L ML Olde Loohuis Loes M LM Ophoff Roel A RA Owen Katharine R KR Packard Chris J CJ Padmanabhan Sandosh S Palmer Colin N A CNA Palmer Nicholette D ND Pasterkamp Gerard G Patel Aniruddh P AP Pattie Alison A Pedersen Oluf O Peissig Peggy L PL Peloso Gina M GM Pennell Craig E CE Perola Markus M Perry James A JA Perry John R B JRB Pers Tune H TH Person Thomas N TN Peters Annette A Petersen Eva R B ERB Peyser Patricia A PA Pirie Ailith A Polasek Ozren O Polderman Tinca J TJ Puolijoki Hannu H Raitakari Olli T OT Rasheed Asif A Rauramaa Rainer R Reilly Dermot F DF Renström Frida F Rheinberger Myriam M Ridker Paul M PM Rioux John D JD Rivas Manuel A MA Roberts David J DJ Robertson Neil R NR Robino Antonietta A Rolandsson Olov O Rudan Igor I Ruth Katherine S KS Saleheen Danish D Salomaa Veikko V Samani Nilesh J NJ Sapkota Yadav Y Sattar Naveed N Schoen Robert E RE Schreiner Pamela J PJ Schulze Matthias B MB Scott Robert A RA Segura-Lepe Marcelo P MP Shah Svati H SH Sheu Wayne H-H WH Sim Xueling X Slater Andrew J AJ Small Kerrin S KS Smith Albert V AV Southam Lorraine L Spector Timothy D TD Speliotes Elizabeth K EK Starr John M JM Stefansson Kari K Steinthorsdottir Valgerdur V Stirrups Kathleen E KE Strauch Konstantin K Stringham Heather M HM Stumvoll Michael M Sun Liang L Surendran Praveen P Swift Amy J AJ Tada Hayato H Tansey Katherine E KE Tardif Jean-Claude JC Taylor Kent D KD Teumer Alexander A Thompson Deborah J DJ Thorleifsson Gudmar G Thorsteinsdottir Unnur U Thuesen Betina H BH Tönjes Anke A Tromp Gerard G Trompet Stella S Tsafantakis Emmanouil E Tuomilehto Jaakko J Tybjaerg-Hansen Anne A Tyrer Jonathan P JP Uher Rudolf R Uitterlinden André G AG Uusitupa Matti M Laan Sander W SW Duijn Cornelia M CM Leeuwen Nienke N van Setten Jessica J Vanhala Mauno M Varbo Anette A Varga Tibor V TV Varma Rohit R Velez Edwards Digna R DR Vermeulen Sita H SH Veronesi Giovanni G Vestergaard Henrik H Vitart Veronique V Vogt Thomas F TF Völker Uwe U Vuckovic Dragana D Wagenknecht Lynne E LE Walker Mark M Wallentin Lars L Wang Feijie F Wang Carol A CA Wang Shuai S Wang Yiqin Y Ware Erin B EB Wareham Nicholas J NJ Warren Helen R HR Waterworth Dawn M DM Wessel Jennifer J White Harvey D HD Willer Cristen J CJ Wilson James G JG Witte Daniel R DR Wood Andrew R AR Wu Ying Y Yaghootkar Hanieh H Yao Jie J Yao Pang P Yerges-Armstrong Laura M LM Young Robin R Zeggini Eleftheria E Zhan Xiaowei X Zhang Weihua W Zhao Jing Hua JH Zhao Wei W Zhao Wei W Zhou Wei W Zondervan Krina T KT Rotter Jerome I JI Pospisilik John A JA Rivadeneira Fernando F Borecki Ingrid B IB Deloukas Panos P Deloukas Panos P Frayling Timothy M TM Lettre Guillaume G North Kari E KE Lindgren Cecilia M CM Hirschhorn Joel N JN Loos Ruth J F RJF

Nature genetics 20171222 1

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 (Z ...[more]

PMID: 29273807

Similar Datasets

Project description:RationaleWe designed a wand-based muscle stretching (WE) exercise program, which has become increasingly popular in physical therapy and has been used for elderly patients with adhesive capsulitis. However, studies regarding the effects of WE training on abdominal obesity and measures of cardiovascular risk factors among overweight/obese adults aged ≥55 years are rare.PurposeThe objective of this study is to evaluate the effects of a 15-week wand stretching exercise program on waist circumference and cardiovascular risk factors in sedentary adults aged 55-70 years.MethodsA total of 124 participants were randomly assigned to either participate in wand stretching exercise (WE) over a 15-week period or a control group (n = 62 each). Sixty participants in the WE group (26 overweight and 34 obese) and 51 in the control group (29 overweight and 22 obese) completed the study. The WE program included wand-assisted muscle stretching exercise on both the upper body and lower body for 40 min per day, 5 days per week, whereas the control group maintained their sedentary lifestyle.ResultsNo significant improvements were observed in plasma glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) after exercise training. Compared with the control group, the WE group had more significant reductions in waist circumference among participants with a body mass index (BMI) < 25 kg/m2 (-2.6 cm, 95% CI: -4.19 to -0.97 cm, d = 0.48) and BMI > 25 kg/m2 (-2.5 cm, 95% CI: -4.1 to -0.9 cm, d = 0.59) (both P < 0.01). Furthermore, within groups, a significant increase in % fat free mass was observed after WE training. The basal metabolic rate was slightly increased, but the fat oxidation rate remained unaltered in the WE group. Improvements in low-density lipoprotein cholesterol to high-density lipoprotein cholesterol were minimal after WE. Significant reductions in high-sensitivity C-reactive protein were observed after WE only for participants with a BMI <25 kg/m2.ConclusionThe results suggest redistribution of a carbon source from the abdominal region to challenged skeletal muscle, following prolonged WE training. This abdominal fat reducing outcome of the WE is unlikely to be associated with fatty acid oxidation.

Project description:PURPOSE:The effects of exergaming-based physical activity (PA) interventions on preschoolers' health outcomes and cognition remain largely unexplored. Therefore, we conducted a randomized controlled trial to discern the effectiveness of a home-based educational exergaming intervention on preschoolers' energy expenditure, fitness, body mass index, and cognition. METHODS:Participants were 32 preschoolers (16 girls; 59.4% Asian; Mage = 4.72, SD = ±0.73) recruited from the Twin Cities area in Minnesota. During baseline testing, we measured preschooler's daily energy expenditure (EE), cardiovascular fitness, body mass index, and cognitive flexibility using validated instruments. Participants were then randomly assigned to one of two conditions: (1) the exergaming intervention condition; or (2) control condition. The intervention program requested children participate in home-based educational exergaming using the LeapTV gaming console for at least 30 min/session 5 times/week. The control condition asked children to maintain regular PA patterns without any exergaming gameplay. Each condition lasted 12 weeks. We conducted identical outcome assessments for all children at baseline and post-intervention. RESULTS:Analysis of covariance with repeated measures yielded significant time x group interaction effects for cognitive flexibility, Wilks' Lambda = 0.81, F(1, 29) = 6.98, p = 0.01, ?2 = 0.19, suggesting children in the exergaming group demonstrated significantly greater increases in cognitive flexibility as compared to those in the control group over time. There were no significant differences for time x group changes between the two groups for EE, Wilks' Lambda = 0.92, F(1, 29) = 2.29, p = 0.14, ?2 = 0.08; cardiovascular fitness, Wilks' Lambda = 0.96, F(1, 29) = 1.07, p = 0.31, ?2 = 0.04; and BMI, Wilks' Lambda = 0.99, F(1, 29) = 0.05, p = 0.82, ?2 = 0.01. However, our data did suggest a marginal effect of time for EE, Wilks' Lambda = 0.89, F(1, 29) = 3.26, p = 0.08, ?2 = 0.08, indicating that children's daily EE increased from baseline to post-intervention. CONCLUSIONS:Home-based educational exergaming may positively impact cognitive flexibility in preschoolers. Studies with larger sample sizes in multiple geographic locations are needed, with our study suggesting a longer intervention period might also be warranted.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure