Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec;49(12):1758-1766.
doi: 10.1038/ng.3977. Epub 2017 Oct 30.

Exome-wide Association Study of Plasma Lipids in >300,000 Individuals

Dajiang J Liu  1 Gina M Peloso  2   3 Haojie Yu  4 Adam S Butterworth  5   6 Xiao Wang  7 Anubha Mahajan  8 Danish Saleheen  5   9   10 Connor Emdin  3   11 Dewan Alam  12 Alexessander Couto Alves  13 Philippe Amouyel  14 Emanuele Di Angelantonio  5   6 Dominique Arveiler  15 Themistocles L Assimes  16   17 Paul L Auer  18 Usman Baber  19 Christie M Ballantyne  20 Lia E Bang  21 Marianne Benn  22   23 Joshua C Bis  24 Michael Boehnke  25 Eric Boerwinkle  26   27 Jette Bork-Jensen  28 Erwin P Bottinger  29 Ivan Brandslund  30   31 Morris Brown  32 Fabio Busonero  33 Mark J Caulfield  32   34   35 John C Chambers  36   37   38 Daniel I Chasman  39   40 Y Eugene Chen  41 Yii-Der Ida Chen  42 Rajiv Chowdhury  5 Cramer Christensen  43 Audrey Y Chu  39   44 John M Connell  45 Francesco Cucca  33   46 L Adrienne Cupples  2   44 Scott M Damrauer  47   48 Gail Davies  49   50 Ian J Deary  49   50 George Dedoussis  51 Joshua C Denny  52   53 Anna Dominiczak  54 Marie-Pierre Dubé  55   56   57 Tapani Ebeling  58 Gudny Eiriksdottir  59 Tõnu Esko  3   60 Aliki-Eleni Farmaki  51 Mary F Feitosa  61 Marco Ferrario  62 Jean Ferrieres  63 Ian Ford  64 Myriam Fornage  65 Paul W Franks  66   67   68 Timothy M Frayling  69 Ruth Frikke-Schmidt  22   23 Lars G Fritsche  25 Philippe Frossard  10 Valentin Fuster  19   70 Santhi K Ganesh  41   71 Wei Gao  72 Melissa E Garcia  73 Christian Gieger  74   75   76 Franco Giulianini  39 Mark O Goodarzi  77   78 Harald Grallert  74   75   76 Niels Grarup  28 Leif Groop  79 Megan L Grove  26 Vilmundur Gudnason  59   80 Torben Hansen  28   81 Tamara B Harris  82 Caroline Hayward  83 Joel N Hirschhorn  3   84 Oddgeir L Holmen  85   86 Jennifer Huffman  83 Yong Huo  87 Kristian Hveem  88 Sehrish Jabeen  10 Anne U Jackson  25 Johanna Jakobsdottir  59   89 Marjo-Riitta Jarvelin  13 Gorm B Jensen  90 Marit E Jørgensen  91   92 J Wouter Jukema  93   94 Johanne M Justesen  28 Pia R Kamstrup  95 Stavroula Kanoni  96 Fredrik Karpe  97   98 Frank Kee  99 Amit V Khera  3   11 Derek Klarin  3   11   100 Heikki A Koistinen  101   102   103 Jaspal S Kooner  37   38   104 Charles Kooperberg  105 Kari Kuulasmaa  101 Johanna Kuusisto  106 Markku Laakso  106 Timo Lakka  107   108   109 Claudia Langenberg  110 Anne Langsted  95   111 Lenore J Launer  82 Torsten Lauritzen  112 David C M Liewald  49   50 Li An Lin  65 Allan Linneberg  113   114   115 Ruth J F Loos  29   116 Yingchang Lu  29 Xiangfeng Lu  41   117 Reedik Mägi  60 Anders Malarstig  118   119 Ani Manichaikul  120 Alisa K Manning  3   11   121 Pekka Mäntyselkä  122 Eirini Marouli  96 Nicholas G D Masca  123   124 Andrea Maschio  33 James B Meigs  3   121   125 Olle Melander  126 Andres Metspalu  60 Andrew P Morris  8   127 Alanna C Morrison  26 Antonella Mulas  33 Martina Müller-Nurasyid  76   128   129 Patricia B Munroe  32   35 Matt J Neville  97 Jonas B Nielsen  41 Sune F Nielsen  95   111 Børge G Nordestgaard  95   111 Jose M Ordovas  130   131   132 Roxana Mehran  19 Christoper J O'Donnell  100   40 Marju Orho-Melander  126 Cliona M Molony  133 Pieter Muntendam  134 Sandosh Padmanabhan  54 Colin N A Palmer  45 Dorota Pasko  69 Aniruddh P Patel  3   11   40   135 Oluf Pedersen  28 Markus Perola  101   136 Annette Peters  74   76   129 Charlotta Pisinger  115 Giorgio Pistis  33 Ozren Polasek  137   138 Neil Poulter  139 Bruce M Psaty  24   140   141 Daniel J Rader  142 Asif Rasheed  10 Rainer Rauramaa  108   109 Dermot F Reilly  133 Alex P Reiner  105   143 Frida Renström  66   144 Stephen S Rich  120 Paul M Ridker  39 John D Rioux  55 Neil R Robertson  8   97 Dan M Roden  52   53 Jerome I Rotter  42 Igor Rudan  138 Veikko Salomaa  101 Nilesh J Samani  123   124 Serena Sanna  33 Naveed Sattar  54   97 Ellen M Schmidt  145 Robert A Scott  110 Peter Sever  139 Raquel S Sevilla  146 Christian M Shaffer  53 Xueling Sim  25   147 Suthesh Sivapalaratnam  148 Kerrin S Small  149 Albert V Smith  59   80 Blair H Smith  150   151 Sangeetha Somayajula  152 Lorraine Southam  8   153 Timothy D Spector  149 Elizabeth K Speliotes  145   154 John M Starr  49   155 Kathleen E Stirrups  96   156 Nathan Stitziel  157   158 Konstantin Strauch  159   160 Heather M Stringham  25 Praveen Surendran  5 Hayato Tada  161 Alan R Tall  162 Hua Tang  163 Jean-Claude Tardif  55   57 Kent D Taylor  42 Stella Trompet  93   164 Philip S Tsao  16   17 Jaakko Tuomilehto  165   166   167   168 Anne Tybjaerg-Hansen  22   23 Natalie R van Zuydam  8   45 Anette Varbo  95   111 Tibor V Varga  66 Jarmo Virtamo  101 Melanie Waldenberger  75   76   129 Nan Wang  162 Nick J Wareham  110 Helen R Warren  32   35 Peter E Weeke  53   169 Joshua Weinstock  25 Jennifer Wessel  170   171 James G Wilson  172 Peter W F Wilson  173   174 Ming Xu  175 Hanieh Yaghootkar  69 Robin Young  5 Eleftheria Zeggini  153 He Zhang  41 Neil S Zheng  176 Weihua Zhang  36 Yan Zhang  87 Wei Zhou  145 Yanhua Zhou  2 Magdalena Zoledziewska  33 Charge Diabetes Working GroupEPIC-InterAct ConsortiumEPIC-CVD ConsortiumGOLD ConsortiumVA Million Veteran ProgramJoanna M M Howson  5 John Danesh  5   6   153 Mark I McCarthy  8   97   98 Chad A Cowan  4   177 Goncalo Abecasis  25 Panos Deloukas  96   178 Kiran Musunuru  7 Cristen J Willer  41   71   145 Sekar Kathiresan  3   11   40   135
Affiliations
Free PMC article

Exome-wide Association Study of Plasma Lipids in >300,000 Individuals

Dajiang J Liu et al. Nat Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1. A1CF p.Gly398Ser mutant leads to increased APOB100 secretion
a, Western blot showing the depletion of endogenous A1CF levels via CRISPR/Cas9 system in both Huh7 and HepG2 cells. b and c, Lack of A1CF leads to reduced APOB100 secretion in Huh7 (b) and HepG2 (c) human hepatoma cells. d, Recombinantly overexpressed A1CF p.Gly398Ser variant led to significantly increased APOB100 secretion compared to A1CF or GFP control in both Huh7 wild-type and A1CF knockout cells (labeled as A1CF KO), respectively. The bars of mean value and error bars of SD are showed in b, c and d from experiments with biological replicates, N=6. Statistically significant differences are marked (*p<0.05, **p<0.01).
Figure 2
Figure 2. Association of genetically-lowered triglycerides by LPL variants with a range of phenotypes
Estimates were derived in UK Biobank using logistic regression, adjusting for age, sex, ten principal components of ancestry and an indicator variable for array type. Effect estimates are for a 1 standard deviation lower plasma triglycerides. Definitions for all outcomes are provided in Supplementary Table 20.

Similar articles

See all similar articles

Cited by 96 articles

See all "Cited by" articles

References

    1. Loh PR, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–90. - PMC - PubMed
    1. Teslovich TM, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13. - PMC - PubMed
    1. Asselbergs FW, et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91:823–38. - PMC - PubMed
    1. Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83. - PMC - PubMed
    1. Albrechtsen A, et al. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia. 2013;56:298–310. - PMC - PubMed

Grant support

Feedback