Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Authors:
Anne E Justice Tugce Karaderi Heather M Highland Kristin L Young Mariaelisa Graff Yingchang Lu Valérie Turcot Paul L Auer Rebecca S Fine Xiuqing Guo Claudia Schurmann Adelheid Lempradl Eirini Marouli Anubha Mahajan Thomas W Winkler Adam E Locke Carolina Medina-Gomez Tõnu Esko Sailaja Vedantam Ayush Giri Ken Sin Lo Tamuno Alfred Poorva Mudgal Maggie C Y Ng Nancy L Heard-Costa Mary F Feitosa Alisa K Manning Sara M Willems Suthesh Sivapalaratnam Goncalo Abecasis Dewan S Alam Matthew Allison Philippe Amouyel Zorayr Arzumanyan Beverley Balkau Lisa Bastarache Sven Bergmann Lawrence F Bielak Matthias Blüher Michael Boehnke Heiner Boeing Eric Boerwinkle Carsten A Böger Jette Bork-Jensen Erwin P Bottinger Donald W Bowden Ivan Brandslund Linda Broer Amber A Burt Adam S Butterworth Mark J Caulfield Giancarlo Cesana John C Chambers Daniel I Chasman Yii-Der Ida Chen Rajiv Chowdhury Cramer Christensen Audrey Y Chu Francis S Collins James P Cook Amanda J Cox David S Crosslin John Danesh Paul I W de Bakker Simon de Denus Renée de Mutsert George Dedoussis Ellen W Demerath Joe G Dennis Josh C Denny Emanuele Di Angelantonio Marcus Dörr Fotios Drenos Marie-Pierre Dubé Alison M Dunning Douglas F Easton Paul Elliott Evangelos Evangelou Aliki-Eleni Farmaki Shuang Feng Ele Ferrannini Jean Ferrieres Jose C Florez Myriam Fornage Caroline S Fox Paul W Franks Nele Friedrich Wei Gan Ilaria Gandin Paolo Gasparini Vilmantas Giedraitis Giorgia Girotto Mathias Gorski Harald Grallert Niels Grarup Megan L Grove Stefan Gustafsson Jeff Haessler Torben Hansen Andrew T Hattersley Caroline Hayward Iris M Heid Oddgeir L Holmen G Kees Hovingh Joanna M M Howson Yao Hu Yi-Jen Hung Kristian Hveem M Arfan Ikram Erik Ingelsson Anne U Jackson Gail P Jarvik Yucheng Jia Torben Jørgensen Pekka Jousilahti Johanne M Justesen Bratati Kahali Maria Karaleftheri Sharon L R Kardia Fredrik Karpe Frank Kee Hidetoshi Kitajima Pirjo Komulainen Jaspal S Kooner Peter Kovacs Bernhard K Krämer Kari Kuulasmaa Johanna Kuusisto Markku Laakso Timo A Lakka David Lamparter Leslie A Lange Claudia Langenberg Eric B Larson Nanette R Lee Wen-Jane Lee Terho Lehtimäki Cora E Lewis Huaixing Li Jin Li Ruifang Li-Gao Li-An Lin Xu Lin Lars Lind Jaana Lindström Allan Linneberg Ching-Ti Liu Dajiang J Liu Jian'an Luan Leo-Pekka Lyytikäinen Stuart MacGregor Reedik Mägi Satu Männistö Gaëlle Marenne Jonathan Marten Nicholas G D Masca Mark I McCarthy Karina Meidtner Evelin Mihailov Leena Moilanen Marie Moitry Dennis O Mook-Kanamori Anna Morgan Andrew P Morris Martina Müller-Nurasyid Patricia B Munroe Narisu Narisu Christopher P Nelson Matt Neville Ioanna Ntalla Jeffrey R O'Connell Katharine R Owen Oluf Pedersen Gina M Peloso Craig E Pennell Markus Perola James A Perry John R B Perry Tune H Pers Ailith Ewing Ozren Polasek Olli T Raitakari Asif Rasheed Chelsea K Raulerson Rainer Rauramaa Dermot F Reilly Alex P Reiner Paul M Ridker Manuel A Rivas Neil R Robertson Antonietta Robino Igor Rudan Katherine S Ruth Danish Saleheen Veikko Salomaa Nilesh J Samani Pamela J Schreiner Matthias B Schulze Robert A Scott Marcelo Segura-Lepe Xueling Sim Andrew J Slater Kerrin S Small Blair H Smith Jennifer A Smith Lorraine Southam Timothy D Spector Elizabeth K Speliotes Kari Stefansson Valgerdur Steinthorsdottir Kathleen E Stirrups Konstantin Strauch Heather M Stringham Michael Stumvoll Liang Sun Praveen Surendran Karin M A Swart Jean-Claude Tardif Kent D Taylor Alexander Teumer Deborah J Thompson Gudmar Thorleifsson Unnur Thorsteinsdottir Betina H Thuesen Anke Tönjes Mina Torres Emmanouil Tsafantakis Jaakko Tuomilehto André G Uitterlinden Matti Uusitupa Cornelia M van Duijn Mauno Vanhala Rohit Varma Sita H Vermeulen Henrik Vestergaard Veronique Vitart Thomas F Vogt Dragana Vuckovic Lynne E Wagenknecht Mark Walker Lars Wallentin Feijie Wang Carol A Wang Shuai Wang Nicholas J Wareham Helen R Warren Dawn M Waterworth Jennifer Wessel Harvey D White Cristen J Willer James G Wilson Andrew R Wood Ying Wu Hanieh Yaghootkar Jie Yao Laura M Yerges-Armstrong Robin Young Eleftheria Zeggini Xiaowei Zhan Weihua Zhang Jing Hua Zhao Wei Zhao He Zheng Wei Zhou M Carola Zillikens Fernando Rivadeneira Ingrid B Borecki J Andrew Pospisilik Panos Deloukas Timothy M Frayling Guillaume Lettre Karen L Mohlke Jerome I Rotter Zoltán Kutalik Joel N Hirschhorn L Adrienne Cupples Ruth J F Loos Kari E North Cecilia M Lindgren

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019
50 Reads
29.352 Impact Factor

Publication Analysis

Top Keywords

body-fat distribution
12
site variants
4
splice site
4
variants exome
4
exome arrays
4
individuals major
4
344369 individuals
4
arrays 344369
4
coding splice
4
predicted coding
4
assessed waist-to-hip
4
distribution assessed
4
waist-to-hip ratio
4
ratio adjusted
4
body mass
4
adjusted body
4
228985 predicted
4
major ancestries
4
frequency maf
4
allele frequency
4

References

(Supplied by CrossRef)

T Pischon et al.
N. Engl. J. Med. 2008

Y Wang et al.
Am. J. Clin. Nutr. 2005

D Canoy et al.
Curr. Opin. Cardiol. 2008

MB Snijder et al.
Am. J. Clin. Nutr. 2003

S Yusuf et al.
Lancet 2005

C Mason et al.
Obesity. 2008

F Karpe et al.
Nat. Rev. Endocrinol. 2015

KN Manolopoulos et al.
Int. J. Obes. 2010

CA Emdin et al.
JAMA 2017

D Shungin et al.
Nature 2015

TW Winkler et al.
PLoS Genet. 2015

Similar Publications