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

Authors:
Dr Eirini Marouli
Dr Eirini Marouli
School of Health Science and Education
Li-An Lin,  PhD
Li-An Lin, PhD
The University of Texas Health Science Center at Houston
He Liang
He Liang
Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules
Mariaelisa Graff Carolina Medina-Gomez Ken Sin Lo Andrew R Wood Troels R Kjaer Rebecca S Fine Yingchang Lu Claudia Schurmann Heather M Highland Sina Rüeger Gudmar Thorleifsson Anne E Justice David Lamparter Kathleen E Stirrups Valérie Turcot Kristin L Young Thomas W Winkler Tõnu Esko Tugce Karaderi Adam E Locke Nicholas G D Masca Maggie C Y Ng Poorva Mudgal Manuel A Rivas Sailaja Vedantam Anubha Mahajan Xiuqing Guo Goncalo Abecasis Katja K Aben Linda S Adair Dewan S Alam Eva Albrecht Kristine H Allin Matthew Allison Philippe Amouyel Emil V Appel Dominique Arveiler Folkert W Asselbergs Paul L Auer Beverley Balkau Bernhard Banas Lia E Bang Marianne Benn Sven Bergmann Lawrence F Bielak Matthias Blüher Heiner Boeing Eric Boerwinkle Carsten A Böger Lori L Bonnycastle Jette Bork-Jensen Michiel L Bots Erwin P Bottinger Donald W Bowden Ivan Brandslund Gerome Breen Murray H Brilliant Linda Broer Amber A Burt Adam S Butterworth David J Carey Mark J Caulfield John C Chambers Daniel I Chasman Yii-Der Ida Chen Rajiv Chowdhury Cramer Christensen Audrey Y Chu Massimiliano Cocca Francis S Collins James P Cook Janie Corley Jordi Corominas Galbany Amanda J Cox Gabriel Cuellar-Partida John Danesh Gail Davies Paul I W de Bakker Gert J de Borst Simon de Denus Mark C H de Groot Renée de Mutsert Ian J Deary George Dedoussis Ellen W Demerath Anneke I den Hollander Joe G Dennis Emanuele Di Angelantonio Fotios Drenos Mengmeng Du Alison M Dunning Douglas F Easton Tapani Ebeling Todd L Edwards Patrick T Ellinor Paul Elliott Evangelos Evangelou Aliki-Eleni Farmaki Jessica D Faul Mary F Feitosa Shuang Feng Ele Ferrannini Marco M Ferrario Jean Ferrieres Jose C Florez Ian Ford Myriam Fornage Paul W Franks Ruth Frikke-Schmidt Tessel E Galesloot Wei Gan Ilaria Gandin Paolo Gasparini Vilmantas Giedraitis Ayush Giri Giorgia Girotto Scott D Gordon Penny Gordon-Larsen Mathias Gorski Niels Grarup Megan L Grove Vilmundur Gudnason Stefan Gustafsson Torben Hansen Kathleen Mullan Harris Tamara B Harris Andrew T Hattersley Caroline Hayward Liang He Iris M Heid Kauko Heikkilä Øyvind Helgeland Jussi Hernesniemi Alex W Hewitt Lynne J Hocking Mette Hollensted Oddgeir L Holmen G Kees Hovingh Joanna M M Howson Carel B Hoyng Paul L Huang Kristian Hveem M Arfan Ikram Erik Ingelsson Anne U Jackson Jan-Håkan Jansson Gail P Jarvik Gorm B Jensen Min A Jhun Yucheng Jia Xuejuan Jiang Stefan Johansson Marit E Jørgensen Torben Jørgensen Pekka Jousilahti J Wouter Jukema Bratati Kahali René S Kahn Mika Kähönen Pia R Kamstrup Stavroula Kanoni Jaakko Kaprio Maria Karaleftheri Sharon L R Kardia Fredrik Karpe Frank Kee Renske Keeman Lambertus A Kiemeney Hidetoshi Kitajima Kirsten B Kluivers Thomas Kocher Pirjo Komulainen Jukka Kontto Jaspal S Kooner Charles Kooperberg Peter Kovacs Jennifer Kriebel Helena Kuivaniemi Sébastien Küry Johanna Kuusisto Martina La Bianca Markku Laakso Timo A Lakka Ethan M Lange Leslie A Lange Carl D Langefeld Claudia Langenberg Eric B Larson I-Te Lee Terho Lehtimäki Cora E Lewis Huaixing Li Jin Li Ruifang Li-Gao Honghuang Lin Xu Lin Lars Lind Jaana Lindström Allan Linneberg Yeheng Liu Yongmei Liu Artitaya Lophatananon Jian'an Luan Steven A Lubitz Leo-Pekka Lyytikäinen David A Mackey Pamela A F Madden Alisa K Manning Satu Männistö Gaëlle Marenne Jonathan Marten Nicholas G Martin Angela L Mazul Karina Meidtner Andres Metspalu Paul Mitchell Karen L Mohlke Dennis O Mook-Kanamori Anna Morgan Andrew D Morris Andrew P Morris Martina Müller-Nurasyid Patricia B Munroe Mike A Nalls Matthias Nauck Christopher P Nelson Matt Neville Sune F Nielsen Kjell Nikus Pål R Njølstad Børge G Nordestgaard Ioanna Ntalla Jeffrey R O'Connel Heikki Oksa Loes M Olde Loohuis Roel A Ophoff Katharine R Owen Chris J Packard Sandosh Padmanabhan Colin N A Palmer Gerard Pasterkamp Aniruddh P Patel Alison Pattie Oluf Pedersen Peggy L Peissig Gina M Peloso Craig E Pennell Markus Perola James A Perry John R B Perry Thomas N Person Ailith Pirie Ozren Polasek Danielle Posthuma Olli T Raitakari Asif Rasheed Rainer Rauramaa Dermot F Reilly Alex P Reiner Frida Renström Paul M Ridker John D Rioux Neil Robertson Antonietta Robino Olov Rolandsson Igor Rudan Katherine S Ruth Danish Saleheen Veikko Salomaa Nilesh J Samani Kevin Sandow Yadav Sapkota Naveed Sattar Marjanka K Schmidt Pamela J Schreiner Matthias B Schulze Robert A Scott Marcelo P Segura-Lepe Svati Shah Xueling Sim Suthesh Sivapalaratnam Kerrin S Small Albert Vernon Smith Jennifer A Smith Lorraine Southam Timothy D Spector Elizabeth K Speliotes John M Starr Valgerdur Steinthorsdottir Heather M Stringham Michael Stumvoll Praveen Surendran Leen M 't Hart Katherine E Tansey Jean-Claude Tardif Kent D Taylor Alexander Teumer Deborah J Thompson Unnur Thorsteinsdottir Betina H Thuesen Anke Tönjes Gerard Tromp Stella Trompet Emmanouil Tsafantakis Jaakko Tuomilehto Anne Tybjaerg-Hansen Jonathan P Tyrer Rudolf Uher André G Uitterlinden Sheila Ulivi Sander W van der Laan Andries R Van Der Leij Cornelia M van Duijn Natasja M van Schoor Jessica van Setten Anette Varbo Tibor V Varga Rohit Varma Digna R Velez Edwards Sita H Vermeulen Henrik Vestergaard Veronique Vitart Thomas F Vogt Diego Vozzi Mark Walker Feijie Wang Carol A Wang Shuai Wang Yiqin Wang Nicholas J Wareham Helen R Warren Jennifer Wessel Sara M Willems James G Wilson Daniel R Witte Michael O Woods Ying Wu Hanieh Yaghootkar Jie Yao Pang Yao Laura M Yerges-Armstrong Robin Young Eleftheria Zeggini Xiaowei Zhan Weihua Zhang Jing Hua Zhao Wei Zhao Wei Zhao He Zheng Wei Zhou Jerome I Rotter Michael Boehnke Sekar Kathiresan Mark I McCarthy Cristen J Willer Kari Stefansson Ingrid B Borecki Dajiang J Liu Kari E North Nancy L Heard-Costa Tune H Pers Cecilia M Lindgren Claus Oxvig Zoltán Kutalik Fernando Rivadeneira Ruth J F Loos Timothy M Frayling Joel N Hirschhorn Panos Deloukas Guillaume Lettre

Nature 2017 02 1;542(7640):186-190. Epub 2017 Feb 1.

Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature21039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302847PMC
February 2017
216 Reads
55 Citations
42.351 Impact Factor

Article Mentions


Provided by Crossref Event Data
f1000
F1000: F1000
September 12, 2017, 8:00 pm EST
reddit-links
Reddit-links: Reddit-links
August 7, 2017, 11:46 am EST
web
Web: Web
March 11, 2017, 10:07 pm EST
twitter
Twitter:
March 25, 2019, 5:41 pm EST
wikipedia
Wikipedia: صفات معقدة (وراثة)
December 6, 2018, 3:22 pm EST
wikipedia
Wikipedia: Draft:Kestutis Rasimavicius
July 8, 2018, 11:03 pm EST
crossref
Crossref: Crossref
June 24, 2018, 8:00 pm EST
wikipedia
Wikipedia: Complex traits
May 4, 2018, 5:54 pm EST
twitter
Twitter: ALT1104
April 7, 2018, 5:46 am EST
wikipedia
Wikipedia: Draft:Raine Study
September 18, 2017, 4:37 am EST
twitter
Twitter: RaineStudy
September 4, 2017, 6:00 pm EST
twitter
Twitter: Markmadsen
July 5, 2017, 3:32 pm EST
twitter
Twitter: Karensunsky
April 25, 2017, 4:19 am EST
twitter
Twitter: Yon_wahyu
April 16, 2017, 3:37 am EST
wikipedia
Wikipedia: Human height
April 12, 2017, 1:56 pm EST
twitter
Twitter: Muneraalfayez
April 8, 2017, 4:51 am EST
twitter
Twitter: Letranger14
March 1, 2017, 11:03 am EST
twitter
Twitter: Inter_xl8s
February 28, 2017, 4:04 am EST
twitter
Twitter: DukeMGM
February 25, 2017, 7:22 pm EST
twitter
Twitter: PavelProsselkov
February 25, 2017, 6:43 pm EST
twitter
Twitter: BioSocialMethod
February 24, 2017, 2:35 pm EST
twitter
Twitter: Ibelda
February 22, 2017, 2:52 pm EST
twitter
Twitter: Khaldoun_ir
February 21, 2017, 3:13 pm EST
twitter
Twitter: Khaldoun_ir
February 21, 2017, 3:09 pm EST
twitter
Twitter: AFornito
February 21, 2017, 2:21 am EST
twitter
Twitter: PNGumich
February 20, 2017, 12:45 pm EST
twitter
Twitter: Xavi_echeverria
February 20, 2017, 12:10 pm EST
twitter
Twitter: ArcadiNavarro
February 20, 2017, 12:08 pm EST

Publication Analysis

Top Keywords

rare low-frequency
8
coding variants
8
variants
7
involved growth
4
height-increasing alleles
4
rare height-increasing
4
studies rare
4
alleles stc2
4
functional follow-up
4
follow-up studies
4
stc2 increase
4
allele compromised
4
glycosaminoglycan synthesis
4
1-2 centimetres allele
4
increase 1-2 centimetres
4
growth demonstrate
4
synthesis involved
4
common variants
4
highlight biological
4
crispld2 greater
4

References

(Supplied by CrossRef)
Article in Trans. R. Soc. Edinb.
RA Fisher et al.
Trans. R. Soc. Edinb. 1918
Article in Twin Res.
K Silventoinen et al.
Twin Res. 2003
Article in Nat. Genet.
AR Wood et al.
Nat. Genet. 2014
Article in Nat. Genet.
J Flannick et al.
Nat. Genet. 2014
Article in Nat. Genet.
V Steinthorsdottir et al.
Nat. Genet. 2014
Article in Nat. Genet.
J Gudmundsson et al.
Nat. Genet. 2012
Article in Nat. Genet.
C Sidore et al.
Nat. Genet. 2015
Article in Nat. Genet.
F Danjou et al.
Nat. Genet. 2015
Article in Proc. Natl Acad. Sci. USA
O Zuk et al.
Proc. Natl Acad. Sci. USA 2014
Article in Nat. Genet.
J Yang et al.
Nat. Genet. 2015
Article in PLoS One
ML Grove et al.
PLoS One 2013

Similar Publications