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

Authors
Dajiang Liu,Gina Peloso
Haojie Yu,Adam Butterworth,Xiao Wang,Anubha Mahajan,Danish Saleheen,Connor Emdin,Dewan Alam,Alexessander Alves,Philippe Amouyel,Emanuele Angelantonio,Dominique Arveiler,Themistocles Assimes,Paul Auer,Usman Baber,Christie Ballantyne,Lia Bang,Marianne Benn,Joshua Bis,Michael Boehnke,Eric Boerwinkle,Jette Bork‐Jensen,Erwin Böttinger,Ivan Brandslund,Morris Brown,Fabio Busonero,Mark Caulfield,John Chambers,Daniel Chasman,Y Chen,Yii‐Der Chen,Rajiv Chowdhury,Cramer Christensen,Audrey Chu,John Connell,Francesco Cucca,L. Cupples,Scott Damrauer,Gail Davies,Ian Deary,George Smith,Joshua Denny,Anna Dominiczak,Marie‐Pierre Dubé,Tapani Ebeling,Guðný Eiríksdóttir,Tõnu Esko,Aliki‐Eleni Farmaki,Mary Feitosa,M Ferrario,Jean Ferrières,Myriam Fornage,Paul Franks,Timothy Frayling,Ruth Frikke‐Schmidt,Lars Fritsche,Philippe Froguel,Valentı́n Fuster,Santhi Ganesh,Wei Gao,Melissa García,Christian Gieger,Anuj Goel,Mark Goodarzi,Harald Grallert,Niels Grarup,Leif Groop,Megan Grove,Vilmundur Guðnason,Torben Hansen,Tamara Harris,Caroline Hayward,Joel Hirschhorn,Oddgeir Holmen,Jennifer Huffman,Yong Huo,Kristian Hveem,Sehrish Jabeen,Anne Jackson,Jóhanna Jakobsdóttir,Marjo‐Riitta Järvelin,Gorm Jensen,Marit Jørgensen,J. Jukema,Johanne Justesen,Pia Kamstrup,Stavroula Kanoni,Fredrik Karpe,Frank Kee,Amit Khera,Derek Klarin,Hannu Koistinen,Jaspal Kooner,Charles Kooperberg,Kari Kuulasmaa,Claudia Langenberg,Markku Laakso,Timo Lakka,Anne Langsted,Lenore Launer,Torsten Lauritzen,David Liewald,Li Lin,Allan Linneberg,Ruth Loos,Yingchang Lu,Xiangfeng Lu,Reedik Mägi,Anders Hamsten,Ani Manichaikul,Alisa Manning,Pekka Mäntyselkä,Eirini Marouli,Nicholas Masca,Andrea Maschio,James Meigs,Olle Melander,Andres Metspalu,Andrew Morris,Alanna Morrison,Antonella Mulas,Martina Müller‐Nurasyid,Patricia Munroe,Matt Neville,Sune Nielsen,Børge Nordestgaard,José Ordovás,Roxana Mehran,Christoper O'Donnell,Marju Orho–Melander,Cliona Molony,Pieter Muntendam,Sandosh Padmanabhan,Colin Palmer,Dorota Pasko,Aniruddh Patel,Oluf Pedersen,Markus Perola,Annette Peters,Charlotta Pisinger,Giorgio Pistis,Ozren Polašek,Neil Poulter,Bruce Psaty,Daniel Rader,Asif Rasheed,Rainer Rauramaa,Dermot Reilly,Alexander Reiner,Frida Renström,Stephen Rich,John Rioux,Neil Robertson,Dan Roden,Jerome Rotter,Igor Rudan,Veikko Salomaa,Nilesh Samani,Serena Sanna,Naveed Sattar,Ellen Schmidt,Robert Scott,Peter Sever,Raquel Sevilla,Christian Shaffer,Xueling Sim,Suthesh Sivapalaratnam,Kerrin Small,Albert Hofman,Blair Smith,Sangeetha Somayajula,Lorraine Southam,Tim Spector,Elizabeth Speliotes,John Starr,Kathleen Stirrups,Nathan Stitziel,Konstantin Strauch,Heather Stringham,Praveen Surendran,Hayato Tada,Alan Tall,Hua Tang,Jean‐Claude Tardif,Kent Taylor,Stella Trompet,Philip Tsao,Jaakko Tuomilehto,Anne Tybjærg‐Hansen,Natalie Zuydam,Jesús Vioqué,Tibor Varga,Jarmo Virtamo,Mélanie Waldenberger,Nan Wang,Nicholas Wareham,Helen Warren,Peter Weeke,Joshua Weinstock,Jennifer Wessel,James Wilson,Peter Wilson,Ming Xu,Hanieh Yaghootkar,Robin Young,Eleftheria Zeggini,He Zhang,Wei Zheng,Weihua Zhang,Qian Zhang,Wei Zhou,Yanhua Zhou,Magdalena Żołędziewska,Joanna Howson,John Danesh,Mark McCarthy,Chad Cowan,Gonçalo Abecasis,Panos Deloukas,Yan Sun,Cristen Willer,Sekar Kathiresan,Dominique Guyader,Yung Chen,Marco Ferrario,Valentín Fuster
+225 authors
,Vilmundur Gudnason
Published
Oct 30, 2017
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Abstract

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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