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Rare and low-frequency coding variants alter human adult height.

ABSTRACT: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2?centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2?centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

SUBMITTER: Marouli E

PROVIDER: S-EPMC5302847 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Rare and low-frequency coding variants alter human adult height.

Marouli Eirini E Graff Mariaelisa M Medina-Gomez Carolina C Lo Ken Sin KS Wood Andrew R AR Kjaer Troels R TR Fine Rebecca S RS Lu Yingchang Y Schurmann Claudia C Highland Heather M HM Rüeger Sina S Thorleifsson Gudmar G Justice Anne E AE Lamparter David D Stirrups Kathleen E KE Turcot Valérie V Young Kristin L KL Winkler Thomas W TW Esko Tõnu T Karaderi Tugce T Locke Adam E AE Masca Nicholas G D NG Ng Maggie C Y MC Mudgal Poorva P Rivas Manuel A MA Vedantam Sailaja S Mahajan Anubha A Guo Xiuqing X Abecasis Goncalo G Aben Katja K KK Adair Linda S LS Alam Dewan S DS Albrecht Eva E Allin Kristine H KH Allison Matthew M Amouyel Philippe P Appel Emil V EV Arveiler Dominique D Asselbergs Folkert W FW Auer Paul L PL Balkau Beverley B Banas Bernhard B Bang Lia E LE Benn Marianne M Bergmann Sven S Bielak Lawrence F LF Blüher Matthias M Boeing Heiner H Boerwinkle Eric E Böger Carsten A CA Bonnycastle Lori L LL 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 Burt Amber A AA Butterworth Adam S AS Carey David J DJ Caulfield Mark J MJ Chambers John C JC Chasman Daniel I DI Chen Yii-Der Ida 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 Galbany Jordi Corominas JC Cox Amanda J AJ Cuellar-Partida Gabriel G Danesh John J Davies Gail G de Bakker Paul I W PI de Borst Gert J GJ de Denus Simon S de Groot Mark C H MC de Mutsert Renée R Deary Ian J IJ Dedoussis George G Demerath Ellen W EW den Hollander Anneke I AI Dennis Joe G JG Di Angelantonio Emanuele E Drenos Fotios F Du Mengmeng M Dunning Alison M AM Easton Douglas F DF Ebeling Tapani T Edwards Todd L TL Ellinor Patrick T PT Elliott Paul P Evangelou Evangelos E Farmaki Aliki-Eleni AE Faul Jessica D JD Feitosa Mary F MF Feng Shuang S Ferrannini Ele E Ferrario Marco M MM Ferrieres Jean J Florez Jose C JC Ford Ian I Fornage Myriam M Franks Paul W PW Frikke-Schmidt Ruth R Galesloot Tessel E TE Gan Wei W Gandin Ilaria I Gasparini Paolo P Giedraitis Vilmantas V Giri Ayush A Girotto Giorgia G Gordon Scott D SD Gordon-Larsen Penny P Gorski Mathias M Grarup Niels N Grove Megan L ML Gudnason Vilmundur V Gustafsson Stefan S Hansen Torben T Harris Kathleen Mullan KM Harris Tamara B TB Hattersley Andrew T AT Hayward Caroline C He Liang L Heid Iris M IM Heikkilä Kauko K Helgeland Øyvind Ø Hernesniemi Jussi J Hewitt Alex W AW Hocking Lynne J LJ Hollensted Mette M Holmen Oddgeir L OL Hovingh G Kees GK Howson Joanna M M JM Hoyng Carel B CB Huang Paul L PL Hveem Kristian K Ikram M Arfan MA Ingelsson Erik E Jackson Anne U AU Jansson Jan-Håkan JH Jarvik Gail P GP Jensen Gorm B GB Jhun Min A MA Jia Yucheng Y Jiang Xuejuan X Johansson Stefan S Jørgensen Marit E ME Jørgensen Torben T Jousilahti Pekka P 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 SL Karpe Fredrik F Kee Frank F Keeman Renske R Kiemeney Lambertus A LA Kitajima Hidetoshi H Kluivers Kirsten B KB Kocher Thomas T Komulainen Pirjo P Kontto Jukka J Kooner Jaspal S JS Kooperberg Charles C Kovacs Peter P Kriebel Jennifer J Kuivaniemi Helena H Küry Sébastien S Kuusisto Johanna J La Bianca Martina M Laakso Markku M Lakka Timo A TA Lange Ethan M EM Lange Leslie A LA Langefeld Carl D CD Langenberg Claudia C Larson Eric B EB Lee I-Te IT Lehtimäki Terho T Lewis Cora E CE Li Huaixing H Li Jin J Li-Gao Ruifang R Lin Honghuang H Lin Li-An LA Lin Xu X Lind Lars L Lindström Jaana J Linneberg Allan A Liu Yeheng Y Liu Yongmei Y Lophatananon Artitaya A Luan Jian'an J Lubitz Steven A SA Lyytikäinen Leo-Pekka LP Mackey David A DA Madden Pamela A F PA Manning Alisa K AK Männistö Satu S Marenne Gaëlle G Marten Jonathan J Martin Nicholas G NG Mazul Angela L AL Meidtner Karina K Metspalu Andres A Mitchell Paul P Mohlke Karen L KL Mook-Kanamori Dennis O DO Morgan Anna A Morris Andrew D AD Morris Andrew P AP Müller-Nurasyid Martina M Munroe Patricia B PB Nalls Mike A MA Nauck Matthias M Nelson Christopher P CP Neville Matt M Nielsen Sune F SF Nikus Kjell K Njølstad Pål R PR Nordestgaard Børge G BG Ntalla Ioanna I O'Connel Jeffrey R JR Oksa Heikki H Loohuis Loes M Olde LM Ophoff Roel A RA Owen Katharine R KR Packard Chris J CJ Padmanabhan Sandosh S Palmer Colin N A CN 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 JR Person Thomas N TN Pirie Ailith A Polasek Ozren O Posthuma Danielle D Raitakari Olli T OT Rasheed Asif A Rauramaa Rainer R Reilly Dermot F DF Reiner Alex P AP Renström Frida F Ridker Paul M PM Rioux John D JD Robertson Neil N Robino Antonietta A Rolandsson Olov O Rudan Igor I Ruth Katherine S KS Saleheen Danish D Salomaa Veikko V Samani Nilesh J NJ Sandow Kevin K Sapkota Yadav Y Sattar Naveed N Schmidt Marjanka K MK Schreiner Pamela J PJ Schulze Matthias B MB Scott Robert A RA Segura-Lepe Marcelo P MP Shah Svati S Sim Xueling X Sivapalaratnam Suthesh S Small Kerrin S KS Smith Albert Vernon AV Smith Jennifer A JA Southam Lorraine L Spector Timothy D TD Speliotes Elizabeth K EK Starr John M JM Steinthorsdottir Valgerdur V Stringham Heather M HM Stumvoll Michael M Surendran Praveen P 't Hart Leen M LM Tansey Katherine E KE Tardif Jean-Claude JC Taylor Kent D KD Teumer Alexander A Thompson Deborah J DJ 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 Ulivi Sheila S van der Laan Sander W SW Van Der Leij Andries R AR van Duijn Cornelia M CM van Schoor Natasja M NM van Setten Jessica J Varbo Anette A Varga Tibor V TV Varma Rohit R Edwards Digna R Velez DR Vermeulen Sita H SH Vestergaard Henrik H Vitart Veronique V Vogt Thomas F TF Vozzi Diego D Walker Mark M Wang Feijie F Wang Carol A CA Wang Shuai S Wang Yiqin Y Wareham Nicholas J NJ Warren Helen R HR Wessel Jennifer J Willems Sara M SM Wilson James G JG Witte Daniel R DR Woods Michael O MO 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 Zheng He H Zhou Wei W Rotter Jerome I JI Boehnke Michael M Kathiresan Sekar S McCarthy Mark I MI Willer Cristen J CJ Stefansson Kari K Borecki Ingrid B IB Liu Dajiang J DJ North Kari E KE Heard-Costa Nancy L NL Pers Tune H TH Lindgren Cecilia M CM Oxvig Claus C Kutalik Zoltán Z Rivadeneira Fernando F Loos Ruth J F RJ Frayling Timothy M TM Hirschhorn Joel N JN Deloukas Panos P Lettre Guillaume G

Nature 20170201 7640

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of ...[more]

PMID: 28146470

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Project description:Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF?<?0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF?=?0.06%; p.Gly71Arg], rs144398951 [MAF?=?0.06%; p.Ile215Val], rs35003977 [MAF?=?0.78%; p.Val225Gly], and rs57307513 [MAF?=?0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P?=?2.34?×?10(-34), P?=?7.02?×?10(-34), and P?=?8.27?×?10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P?=?1.98?×?10(-26); rs2070959, p.Thr181Ala, P?=?2.87?×?10(-27); and rs1105879, p.Arg184Ser, P?=?3.27?×?10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P?=?3.21?×?10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

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Rare and low-frequency coding variants alter human adult height.

Publications

Rare and low-frequency coding variants alter human adult height.

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