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Meta-Analysis
. 2019 Jun 1;188(6):1033-1054.
doi: 10.1093/aje/kwz005.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Paul S de Vries  1 , Michael R Brown  1 , Amy R Bentley  2 , Yun J Sung  3 , Thomas W Winkler  4 , Ioanna Ntalla  5 , Karen Schwander  3 , Aldi T Kraja  6 , Xiuqing Guo  7 , Nora Franceschini  8 , Ching-Yu Cheng  9   10   11 , Xueling Sim  12 , Dina Vojinovic  13 , Jennifer E Huffman  14 , Solomon K Musani  15 , Changwei Li  16 , Mary F Feitosa  6 , Melissa A Richard  17 , Raymond Noordam  18 , Hugues Aschard  19   20 , Traci M Bartz  21 , Lawrence F Bielak  22 , Xuan Deng  23 , Rajkumar Dorajoo  24 , Kurt K Lohman  25 , Alisa K Manning  26   27 , Tuomo Rankinen  28 , Albert V Smith  29   30 , Salman M Tajuddin  31 , Evangelos Evangelou  32   33 , Mariaelisa Graff  8 , Maris Alver  34 , Mathilde Boissel  35 , Jin Fang Chai  12 , Xu Chen  36 , Jasmin Divers  37 , Ilaria Gandin  38 , Chuan Gao  39 , Anuj Goel  40   41 , Yanick Hagemeijer  42 , Sarah E Harris  43   44 , Fernando P Hartwig  45   46 , Meian He  47 , Andrea R V R Horimoto  48 , Fang-Chi Hsu  37 , Anne U Jackson  49 , Anuradhani Kasturiratne  50 , Pirjo Komulainen  51 , Brigitte Kühnel  52   53 , Federica Laguzzi  54 , Joseph H Lee  55 , Jian'an Luan  56 , Leo-Pekka Lyytikäinen  57   58 , Nana Matoba  59 , Ilja M Nolte  60 , Maik Pietzner  61   62 , Muhammad Riaz  63   64 , M Abdullah Said  42 , Robert A Scott  56 , Tamar Sofer  27   65 , Alena Stančáková  66 , Fumihiko Takeuchi  67 , Bamidele O Tayo  68 , Peter J van der Most  60 , Tibor V Varga  69 , Yajuan Wang  70 , Erin B Ware  71 , Wanqing Wen  72 , Lisa R Yanek  73 , Weihua Zhang  32   74 , Jing Hua Zhao  56 , Saima Afaq  32 , Najaf Amin  13 , Marzyeh Amini  60 , Dan E Arking  75 , Tin Aung  9   11   76 , Christie Ballantyne  77   78 , Eric Boerwinkle  79   80 , Ulrich Broeckel  81 , Archie Campbell  82 , Mickaël Canouil  35 , Sabanayagam Charumathi  9   10 , Yii-Der Ida Chen  7 , John M Connell  83 , Ulf de Faire  54 , Lisa de las Fuentes  3   84 , Renée de Mutsert  85 , H Janaka de Silva  86 , Jingzhong Ding  87 , Anna F Dominiczak  88 , Qing Duan  89 , Charles B Eaton  90 , Ruben N Eppinga  42 , Jessica D Faul  71 , Virginia Fisher  23 , Terrence Forrester  91 , Oscar H Franco  13   92 , Yechiel Friedlander  93 , Mohsen Ghanbari  13   94 , Franco Giulianini, Hans J Grabe  95 , Megan L Grove  1 , C Charles Gu  3 , Tamara B Harris  96 , Sami Heikkinen  66   97 , Chew-Kiat Heng  98   99 , Makoto Hirata  100 , James E Hixson  79 , Barbara V Howard  101   102 , M Arfan Ikram  13   103   104 ; InterAct Consortium; David R Jacobs  105 , Craig Johnson  106 , Jost Bruno Jonas  107   108 , Candace M Kammerer  109 , Tomohiro Katsuya  110   111 , Chiea Chuen Khor  24   112 , Tuomas O Kilpeläinen  113   114 , Woon-Puay Koh  12   115 , Heikki A Koistinen  116   117   118 , Ivana Kolcic, Charles Kooperberg  119 , Jose E Krieger  48 , Steve B Kritchevsky  120 , Michiaki Kubo  121 , Johanna Kuusisto  66 , Timo A Lakka  51   97   122 , Carl D Langefeld  37 , Claudia Langenberg  56 , Lenore J Launer  96 , Benjamin Lehne  32 , Rozenn N Lemaitre  123 , Yize Li  3 , Jingjing Liang  70 , Jianjun Liu  24   124 , Kiang Liu  125 , Marie Loh  32   126 , Tin Louie  127 , Reedik Mägi  34 , Ani W Manichaikul  128 , Colin A McKenzie  91 , Thomas Meitinger  129   130 , Andres Metspalu  34 , Yuri Milaneschi  131 , Lili Milani  34 , Karen L Mohlke  89 , Thomas H Mosley  132 , Kenneth J Mukamal  133 , Mike A Nalls  134   135 , Matthias Nauck  61   62 , Christopher P Nelson  63   64 , Nona Sotoodehnia  136 , Jeff R O'Connell  137   138 , Nicholette D Palmer  139 , Raha Pazoki  32 , Nancy L Pedersen  36 , Annette Peters  53   62 , Patricia A Peyser  22 , Ozren Polasek  140   141   142 , Neil Poulter  143 , Leslie J Raffel  144 , Olli T Raitakari  145   146 , Alex P Reiner  119 , Treva K Rice  3 , Stephen S Rich  147 , Antonietta Robino  148 , Jennifer G Robinson  149 , Lynda M Rose  150 , Igor Rudan  151 , Carsten O Schmidt  152 , Pamela J Schreiner  105 , William R Scott  32   153 , Peter Sever  153 , Yuan Shi  9 , Stephen Sidney  154 , Mario Sims  15 , Blair H Smith  155 , Jennifer A Smith  22   71 , Harold Snieder  60 , John M Starr  43   156 , Konstantin Strauch  157   158 , Nicholas Tan  9   11 , Kent D Taylor  7 , Yik Ying Teo  12   24   159   160   161 , Yih Chung Tham  9 , André G Uitterlinden  13   162 , Diana van Heemst  18 , Dragana Vuckovic  38 , Melanie Waldenberger  52   53 , Lihua Wang  6 , Yujie Wang  8 , Zhe Wang  1 , Wen Bin Wei  163 , Christine Williams  6 , Gregory Wilson  164 , Mary K Wojczynski  6 , Jie Yao  7 , Bing Yu  1 , Caizheng Yu  47 , Jian-Min Yuan  165   166 , Wei Zhao  22 , Alan B Zonderman  167 , Diane M Becker  73 , Michael Boehnke  49 , Donald W Bowden  139 , John C Chambers  32   74   168   169   170   171 , Ian J Deary  43   172 , Tõnu Esko  34   173 , Martin Farrall  40   41 , Paul W Franks  69   174   175   176 , Barry I Freedman  177 , Philippe Froguel  35   178 , Paolo Gasparini  38   148 , Christian Gieger  52   179 , Bernardo L Horta  45 , Yoichiro Kamatani  59 , Norihiro Kato  67 , Jaspal S Kooner  74   153   169   171 , Markku Laakso  66 , Karin Leander  54 , Terho Lehtimäki  57   58 ; Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study); Patrik K E Magnusson  36 , Brenda Penninx  131 , Alexandre C Pereira  48 , Rainer Rauramaa  51 , Nilesh J Samani  63   64 , James Scott  153 , Xiao-Ou Shu  72 , Pim van der Harst  42   180 , Lynne E Wagenknecht  181 , Ya Xing Wang  182 , Nicholas J Wareham  56 , Hugh Watkins  40   41 , David R Weir  71 , Ananda R Wickremasinghe  50 , Wei Zheng  72 , Paul Elliott  32   170   171   183   184 , Kari E North  8   185 , Claude Bouchard  28 , Michele K Evans  31 , Vilmundur Gudnason  29   30 , Ching-Ti Liu  23 , Yongmei Liu  186 , Bruce M Psaty  187   188 , Paul M Ridker  150   189 , Rob M van Dam  12   174   124 , Sharon L R Kardia  22 , Xiaofeng Zhu  70 , Charles N Rotimi  2 , Dennis O Mook-Kanamori  85   190 , Myriam Fornage  1   17 , Tanika N Kelly  191 , Ervin R Fox  192 , Caroline Hayward  14 , Cornelia M van Duijn  13 , E Shyong Tai  12   115   124 , Tien Yin Wong  9   11   76 , Jingmin Liu  193 , Jerome I Rotter  7 , W James Gauderman  194 , Michael A Province  6 , Patricia B Munroe  5   195 , Kenneth Rice  127 , Daniel I Chasman  150   189 , L Adrienne Cupples  23   196 , Dabeeru C Rao  3 , Alanna C Morrison  1
Affiliations
Meta-Analysis

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Paul S de Vries et al. Am J Epidemiol. .

Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Keywords: alcohol consumption; cholesterol; gene-environment interactions; gene-lifestyle interactions; genome-wide association studies; lipids; triglycerides.

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Figures

Figure 1.
Figure 1.
Distribution of genome-wide-significant associations at 147 genetic loci identified as being associated with 3 lipid traits (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides) in a genome-wide meta-analysis of gene-alcohol interaction and lipid levels, 2017.
Figure 2.
Figure 2.
Significance and direction of effects of index genetic variants identified at 18 novel loci for 3 lipid traits (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)) in a genome-wide meta-analysis of gene-alcohol interaction and lipid levels, 2017. For each combination of index variant and lipid trait, the effect direction of and P value for the most significant association is shown. For example, the rs11:63911273 variant was most significantly associated with HDL-C in the transancestry meta-analysis, using the “current drinker” alcohol consumption variable. Shades of purple and yellow represent negative and positive directions of effect, respectively, while associations of either direction with a P value greater than 0.05 are white. Effect +: the direction of effect is greater than or equal to zero; Effect –: the direction of effect is less than zero. df, degrees of freedom; ID, identification; rs, reference SNP; SNP, single nucleotide polymorphism.
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References

    1. Roth GA, Johnson C, Abajobir A, et al. . Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990–2015. J Am Coll Cardiol. 2017;70(1):1–25. - PMC - PubMed
    1. Asselbergs FW, Guo Y, van Iperen EP, et al. . Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet. 2012;91(5):823–838. - PMC - PubMed
    1. Global Lipids Genetics Consortium, Willer CJ, Schmidt EM, et al. . Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45(11):1274–1283. - PMC - PubMed
    1. Peloso GM, Auer PL, Bis JC, et al. . Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014;94(2):223–232. - PMC - PubMed
    1. Spracklen CN, Chen P, Kim YJ, et al. . Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels. Hum Mol Genet. 2017;26(9):1770–1784. - PMC - PubMed

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