Exome-wide association study of plasma lipids in >300,000 individuals.

Authors:
Dajiang J Liu Gina M Peloso Haojie Yu Adam S Butterworth Xiao Wang Anubha Mahajan Danish Saleheen Connor Emdin Dewan Alam Alexessander Couto Alves Philippe Amouyel Emanuele Di Angelantonio Dominique Arveiler Themistocles L Assimes Paul L Auer Usman Baber Christie M Ballantyne Lia E Bang Marianne Benn Joshua C Bis Michael Boehnke Eric Boerwinkle Jette Bork-Jensen Erwin P Bottinger Ivan Brandslund Morris Brown Fabio Busonero Mark J Caulfield John C Chambers Daniel I Chasman Y Eugene Chen Yii-Der Ida Chen Rajiv Chowdhury Cramer Christensen Audrey Y Chu John M Connell Francesco Cucca L Adrienne Cupples Scott M Damrauer Gail Davies Ian J Deary George Dedoussis Joshua C Denny Anna Dominiczak Marie-Pierre Dubé Tapani Ebeling Gudny Eiriksdottir Tõnu Esko Aliki-Eleni Farmaki Mary F Feitosa Marco Ferrario Jean Ferrieres Ian Ford Myriam Fornage Paul W Franks Timothy M Frayling Ruth Frikke-Schmidt Lars G Fritsche Philippe Frossard Valentin Fuster Santhi K Ganesh Wei Gao Melissa E Garcia Christian Gieger Franco Giulianini Mark O Goodarzi Harald Grallert Niels Grarup Leif Groop Megan L Grove Vilmundur Gudnason Torben Hansen Tamara B Harris Caroline Hayward Joel N Hirschhorn Oddgeir L Holmen Jennifer Huffman Yong Huo Kristian Hveem Sehrish Jabeen Anne U Jackson Johanna Jakobsdottir Marjo-Riitta Jarvelin Gorm B Jensen Marit E Jørgensen J Wouter Jukema Johanne M Justesen Pia R Kamstrup Stavroula Kanoni Fredrik Karpe Frank Kee Amit V Khera Derek Klarin Heikki A Koistinen Jaspal S Kooner Charles Kooperberg Kari Kuulasmaa Johanna Kuusisto Markku Laakso Timo Lakka Claudia Langenberg Anne Langsted Lenore J Launer Torsten Lauritzen David C M Liewald Li An Lin Allan Linneberg Ruth J F Loos Yingchang Lu Xiangfeng Lu Reedik Mägi Anders Malarstig Ani Manichaikul Alisa K Manning Pekka Mäntyselkä Eirini Marouli Nicholas G D Masca Andrea Maschio James B Meigs Olle Melander Andres Metspalu Andrew P Morris Alanna C Morrison Antonella Mulas Martina Müller-Nurasyid Patricia B Munroe Matt J Neville Jonas B Nielsen Sune F Nielsen Børge G Nordestgaard Jose M Ordovas Roxana Mehran Christoper J O'Donnell Marju Orho-Melander Cliona M Molony Pieter Muntendam Sandosh Padmanabhan Colin N A Palmer Dorota Pasko Aniruddh P Patel Oluf Pedersen Markus Perola Annette Peters Charlotta Pisinger Giorgio Pistis Ozren Polasek Neil Poulter Bruce M Psaty Daniel J Rader Asif Rasheed Rainer Rauramaa Dermot F Reilly Alex P Reiner Frida Renström Stephen S Rich Paul M Ridker John D Rioux Neil R Robertson Dan M Roden Jerome I Rotter Igor Rudan Veikko Salomaa Nilesh J Samani Serena Sanna Naveed Sattar Ellen M Schmidt Robert A Scott Peter Sever Raquel S Sevilla Christian M Shaffer Xueling Sim Suthesh Sivapalaratnam Kerrin S Small Albert V Smith Blair H Smith Sangeetha Somayajula Lorraine Southam Timothy D Spector Elizabeth K Speliotes John M Starr Kathleen E Stirrups Nathan Stitziel Konstantin Strauch Heather M Stringham Praveen Surendran Hayato Tada Alan R Tall Hua Tang Jean-Claude Tardif Kent D Taylor Stella Trompet Philip S Tsao Jaakko Tuomilehto Anne Tybjaerg-Hansen Natalie R van Zuydam Anette Varbo Tibor V Varga Jarmo Virtamo Melanie Waldenberger Nan Wang Nick J Wareham Helen R Warren Peter E Weeke Joshua Weinstock Jennifer Wessel James G Wilson Peter W F Wilson Ming Xu Hanieh Yaghootkar Robin Young Eleftheria Zeggini He Zhang Neil S Zheng Weihua Zhang Yan Zhang Wei Zhou Yanhua Zhou Magdalena Zoledziewska Joanna M M Howson John Danesh Mark I McCarthy Chad A Cowan Goncalo Abecasis Panos Deloukas Kiran Musunuru Cristen J Willer Sekar Kathiresan

Nat Genet 2017 Dec 30;49(12):1758-1766. Epub 2017 Oct 30.

Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

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Source
http://dx.doi.org/10.1038/ng.3977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709146PMC
December 2017
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Publication Analysis

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References

(Supplied by CrossRef)
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Nature 2010
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FW Asselbergs et al.
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Article in Nat. Genet.
CJ Willer et al.
Nat. Genet. 2013
Article in Diabetologia
A Albrechtsen et al.
Diabetologia 2013
Article in Am. J. Hum. Genet.
GM Peloso et al.
Am. J. Hum. Genet. 2014
Article in Nat. Genet.
I Surakka et al.
Nat. Genet. 2015
Article in Nat. Commun.
CS Tang et al.
Nat. Commun. 2015
Article in Nature
K Musunuru et al.
Nature 2010
Article in J. Clin. Invest.
R Burkhardt et al.
J. Clin. Invest. 2010
Article in Lancet
BF Voight et al.
Lancet 2012
Article in Nat. Genet.
R Do et al.
Nat. Genet. 2013

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