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Volume 47 Issue 12
Dec.  2020
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Article Contents

Fine genetic mapping of the chromosome 11q23.3 region in a Han Chinese population: insights into the apolipoprotein genes underlying the blood lipid-lipoprotein variances

doi: 10.1016/j.jgg.2020.11.010
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  • The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediateAPOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population.
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  • [1]
    Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., Suzuki, T., Ntini, E., Arner, E., Valen, E., Li, K., Schwarzfischer, L., Glatz, D., Raithel, J., Lilje, B., Rapin, N., Bagger, F.O., Joergensen, M., Andersen, P.R., Bertin, N., Rackham, O., Burroughs, A.M., Baillie, J.K., Ishizu, Y., Shimizu, Y., Furuhata, E., Maeda, S., Negishi, Y., Mungall, C.J., Meehan, T.F., Lassmann, T., Itoh, M., Kawaji, H., Kondo, N., Kawai, J., Lennartsson, A., Daub, C.O., Heutink, P., Hume, D.A., Jensen, T.H., Suzuki, H., Hayashizaki, Y., Muller, F., Forrest, A.R.R., Carninci, P., Rehli, M., Sandelin, A., 2014. An atlas of active enhancers across human cell types and tissues. Nature 507, 455-461.
    [2]
    Bentley, A.R., Sung, Y.J., Brown, M.R., Winkler, T.W., Kraja, A.T., Ntalla, I., Schwander, K., Chasman, D.I., Lim, E., Deng, X., Guo, X., Liu, J., Lu, Y., Cheng, C.Y., Sim, X., Vojinovic, D., Huffman, J.E., Musani, S.K., Li, C., Feitosa, M.F., Richard, M.A., Noordam, R., Baker, J., Chen, G., Aschard, H., Bartz, T.M., Ding, J., Dorajoo, R., Manning, A.K., Rankinen, T., Smith, A.V., Tajuddin, S.M., Zhao, W., Graff, M., Alver, M., Boissel, M., Chai, J.F., Chen, X., Divers, J., Evangelou, E., Gao, C., Goel, A., Hagemeijer, Y., Harris, S.E., Hartwig, F.P., He, M., Horimoto, A.R.V.R., Hsu, F.C., Hung, Y.J., Jackson, A.U., Kasturiratne, A., Komulainen, P., Kuhnel B., Leander, K., Lin, K.H., Luan, J., Lyytikainen, L.P., Matoba, N., Nolte, I.M., Pietzner, M., Prins, B., Riaz, M., Robino, A., Said, M.A., Schupf, N., Scott, R.A., Sofer, T., Stancakova, A., Takeuchi, F., Tayo, B.O., van der Most, P.J., Varga, T.V., Wang, T.D., Wang, Y., Ware, E.B., Wen, W., Xiang, Y.B., Yanek, L.R., Zhang, W., Zhao, J.H., Adeyemo, A., Afaq, S., Amin, N., Amini, M., Arking, D.E., Arzumanyan, Z., Aung, T., Ballantyne, C., Barr, R.G., Bielak, L.F., Boerwinkle, E., Bottinger, E.P., Broeckel, U., Brown, M., Cade, B.E., Campbell, A., Canouil, M., Charumathi, S., Chen, Y.I., Christensen, K.; COGENT-Kidney Consortium, Concas, M.P., Connell, J.M., de Las Fuentes, L., de Silva, H.J., de Vries, P.S., Doumatey, A., Duan, Q., Eaton, C.B., Eppinga, R.N., Faul, J.D., Floyd, J.S., Forouhi, N.G., Forrester, T., Friedlander, Y., Gandin, I., Gao, H., Ghanbari, M., Gharib, S.A., Gigante, B., Giulianini, F., Grabe, H.J., Gu, C.C., Harris, T.B., Heikkinen, S., Heng, C.K., Hirata, M., Hixson, J.E., Ikram, M.A.; EPIC-InterAct Consortium, Jia, Y., Joehanes, R., Johnson, C., Jonas, J.B., Justice, A.E., Katsuya, T., Khor, C.C., Kilpelainen, T.O., Koh, W.P., Kolcic, I., Kooperberg, C., Krieger, J.E., Kritchevsky, S.B., Kubo, M., Kuusisto, J., Lakka, T.A., Langefeld, C.D., Langenberg, C., Launer, L.J., Lehne, B., Lewis, C.E., Li, Y., Liang, J., Lin, S., Liu, C.T., Liu, J., Liu, K., Loh, M., Lohman, K.K., Louie, T., Luzzi, A., Magi, R., Mahajan, A., Manichaikul, A.W., McKenzie, C.A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mohlke, K.L., Momozawa, Y., Morris, A.P., Murray, A.D., Nalls, M.A., Nauck, M., Nelson, C.P., North, K.E., O'Connell, J.R., Palmer, N.D., Papanicolau, G.J., Pedersen, N.L., Peters, A., Peyser, P.A., Polasek, O., Poulter, N., Raitakari, O.T., Reiner, A.P., Renstrom, F., Rice, T.K., Rich, S.S., Robinson, J.G., Rose, L.M., Rosendaal, F.R., Rudan, I., Schmidt, C.O., Schreiner, P.J., Scott, W.R., Sever, P., Shi, Y., Sidney, S., Sims, M., Smith, J.A., Snieder, H., Starr, J.M., Strauch, K., Stringham, H.M., Tan, N.Y.Q., Tang, H., Taylor, K.D., Teo, Y.Y., Tham, Y.C., Tiemeier, H., Turner, S.T., Uitterlinden, A.G.; Understanding Society Scientific Group, van Heemst, D., Waldenberger, M., Wang, H., ang, L., Wang, L., Wei, W.B., Williams, C.A., Wilson, G. Sr., Wojczynski, M.K., Yao, J., Young, K., Yu, C., Yuan, J.M., Zhou, J., Zonderman, A.B., Becker, D.M., Boehnke, M., Bowden, D.W., Chambers, J.C., Cooper, R.S., de Faire, U., Deary, I.J., Elliott, P., Esko, T., Farrall, M., Franks, P.W., Freedman, B.I., Froguel, P., Gasparini, P., Gieger, C., Horta, B.L., Juang, J.J., Kamatani, Y., Kammerer, C.M., Kato, N., Kooner, J.S., Laakso, M., Laurie, C.C., Lee, I.T., Lehtimaki, T.; Lifelines Cohort, Magnusson, P.K.E., Oldehinkel, A.J., Penninx, B.W.J.H., Pereira, A.C., Rauramaa, R., Redline, S., Samani, N.J., Scott, J., Shu, X.O., van der Harst, P., Wagenknecht, L.E., Wang, J.S., Wang, Y.X., Wareham, N.J., Watkins, H., Weir, D.R., Wickremasinghe, A.R., Wu, T., Zeggini, E., Zheng, W., Bouchard, C., Evans, M.K., Gudnason, V., Kardia, S.L.R., Liu, Y., Psaty, B.M., Ridker, P.M., van Dam, R.M., Mook-Kanamori, D.O., Fornage, M., Province, M.A., Kelly, T.N., Fox, E.R., Hayward, C., van Duijn, C.M., Tai, E.S., Wong, T.Y., Loos, R.J.F., Franceschini, N., Rotter, J.I., Zhu, X., Bierut, L.J., Gauderman, W.J., Rice, K., Munroe, P.B., Morrison, A.C., Rao, D.C., Rotimi, C.N., Cupples, L.A., 2019. Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. Nat. Genet. 51, 636-648.
    [3]
    Bonder, M.J., Luijk, R., Zhernakova, D.V., Moed, M., Deelen, P., Vermaat, M., van Iterson, M., van Dijk, F., van Galen, M., Bot, J., Slieker, R.C., Jhamai, P.M., Verbiest, M., Suchiman, H.E., Verkerk, M., van der Breggen, R., van Rooij, J., Lakenberg, N., Arindrarto, W., Kielbasa, S.M., Jonkers, I., van 't Hof, P., Nooren, I. , Beekman, M., Deelen, J., van Heemst, D., Zhernakova, A., Tigchelaar, E.F., Swertz, M.A., Hofman, A., Uitterlinden, A.G., Pool, R., van Dongen, J., Hottenga, J.J., Stehouwer, C.D., van der Kallen, C.J., Schalkwijk, C.G., van den Berg, L.H., van Zwet, E.W., Mei, H., Li, Y., Lemire, M., Hudson, T.J.; BIOS Consortium, Slagboom, P.E. , Wijmenga, C., Veldink, J.H., van Greevenbroek, M.M., van Duijn, C.M., Boomsma, D.I., Isaacs, A., Jansen, R., van Meurs, J.B., 't Hoen, P.A., Franke, L., Heijmans, B.T., 2017. Disease variants alter transcription factor levels and methylation of their binding sites. Nat. Genet. 49, 131-138.
    [4]
    Boyle, A.P., Hong, E.L., Hariharan, M., Cheng, Y., Schaub, M.A., Kasowski, M., Karczewski, K.J., Park, J., Hitz, B.C., Weng, S., Cherry, J.M., Snyder, M., 2012. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790-1797.
    [5]
    Cannon, M.E., Mohlke, K.L., 2018. Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci. Am. J. Hum. Genet. 103, 637-653.
    [6]
    Caussy, C., Charriere, S., Marcais, C., Di Filippo, M., Sassolas, A., Delay, M., Euthine, V., Jalabert, A., Lefai, E., Rome, S., Moulin, P., 2014. An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site. Am. J. Hum. Genet. 94, 129-134.
    [7]
    Chapman, M.J., Ginsberg, H.N., Amarenco, P., Andreotti, F., Boren, J., Catapano, A.L., Descamps, O.S., Fisher, E., Kovanen, P.T., Kuivenhoven, J.A., Lesnik, P., Masana, L., Nordestgaard, B.G., Ray, K.K., Reiner, Z., Taskinen, M.R., Tokgozoglu, L., Tybjaerg-Hansen, A., Watts, G.F.; European Atherosclerosis Society Consensus Panel, 2011. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart. J. 32, 1345-1361.
    [8]
    Crosby, J., Peloso, G.M., Auer, P.L., Crosslin, D.R., Stitziel, N.O., Lange, L.A., Lu, Y., Tang, Z.Z., Zhang, H., Hindy, G., Masca, N., Stirrups, K., Kanoni, S., Do, R., Jun, G., Hu, Y., Kang, H.M., Xue, C., Goel, A., Farrall, M., Duga, S., Merlini, P.A., Asselta, R., Girelli, D., Olivieri, O., Martinelli, N., Yin, W., Reilly, D., Speliotes, E., Fox, C.S., Hveem, K., Holmen, O.L., Nikpay, M., Farlow, D.N., Assimes, T.L., Franceschini, N., Robinson, J., North, K.E., Martin, L.W., DePristo, M., Gupta, N., Escher, S.A., Jansson, J.H., Van Zuydam, N., Palmer, C.N., Wareham, N., Koch, W., Meitinger, T., Peters, A., Lieb, W., Erbel, R., Konig, I.R., Kruppa, J., Degenhardt, F., Gottesman, O., Bottinger, E.P., O'Donnell, C.J., Psaty, B.M., Ballantyne, C.M., Abecasis, G., Ordovas, J.M., Melander, O., Watkins, H., Orho-Melander, M., Ardissino, D., Loos, R.J., McPherson, R., Willer, C.J., Erdmann, J., Hall, A.S., Samani, N.J., Deloukas, P., Schunkert, H., Wilson, J.G., Kooperberg, C., Rich, S.S., Tracy, R.P., Lin, D.Y., Altshuler, D., Gabriel, S., Nickerson, D.A., Jarvik, G.P., Cupples, L.A., Reiner, A.P., Boerwinkle, E., Kathiresan, S., TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, 2014. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22-31.
    [9]
    Di Angelantonio, E., Sarwar, N., Perry, P., 2009. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993-2000.
    [10]
    Do, R., Stitziel, N.O., Won, H.H., Joergensen, A.B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., Lange, L.A., Peloso, G.M., Auer, P.L.; NHLBI Exome Sequencing Project, Girelli, D., Martinelli, N., Farlow, D.N., DePristo, M.A., Roberts, R., Stewart, A.F., Saleheen, D., Danesh, J., Epstein, S.E., Sivapalaratnam, S., Hovingh, G.K., Kastelein, J.J., Samani, N.J., Schunkert, H., Erdmann, J., Shah, S.H., Kraus, W.E., Davies, R., Nikpay, M., Johansen, C.T., Wang, J., Hegele, R.A., Hechter, E., Marz, W., Kleber, M.E., Huang, J., Johnson, A.D., Li, M., Burke, G.L., Gross, M., Liu, Y., Assimes, T.L., Heiss, G., Lange, E.M., Folsom, A.R., Taylor, H.A., Olivieri, O., Hamsten, A., Clarke, R., Reilly, D.F., Yin, W., Rivas, M.A., Donnelly, P., Rossouw, J.E., Psaty, B.M., Herrington, D.M., Wilson, J.G., Rich, S.S., Bamshad, M.J., Tracy, R.P., Cupples, L.A., Rader, D.J., Reilly, M.P., Spertus, J.A., Cresci, S., Hartiala, J., Tang, W.H., Hazen, S.L., Allayee, H., Reiner, A.P., Carlson, C.S., Kooperberg, C., Jackson, R.D., Boerwinkle, E., Lander, E.S., Schwartz, S.M., Siscovick, D.S., McPherson, R., Tybjaerg-Hansen, A., Abecasis, G.R., Watkins, H., Nickerson, D.A., Ardissino, D., Sunyaev, S.R., O'Donnell, C.J., Altshuler, D., Gabriel, S., Kathiresan, S., 2015. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102-106.
    [11]
    Edmondson, A.C., Braund, P.S., Stylianou, I.M., Khera, A.V., Nelson, C.P., Wolfe, M.L., Derohannessian, S.L., Keating, B.J., Qu, L., He, J., Tobin, M.D., Tomaszewski, M., Baumert, J., Klopp, N., Doring, A., Thorand, B., Li, M., Reilly, M.P., Koenig, W., Samani, N.J., Rader, D.J., 2011. Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol. Circ. Cardiovasc. Genet. 4, 145-155.
    [12]
    Elbers, C.C., Guo, Y., Tragante, V., van Iperen, E.P., Lanktree, M.B., Castillo, B.A., Chen, F., Yanek, L.R., Wojczynski, M.K., Li, Y.R., Ferwerda, B., Ballantyne, C.M., Buxbaum, S.G., Chen, Y.D., Chen, W.M., Cupples, L.A., Cushman, M., Duan, Y., Duggan, D., Evans, M.K., Fernandes, J.K., Fornage, M., Garcia, M., Garvey, W.T., Glazer, N., Gomez, F., Harris, T.B., Halder, I., Howard, V.J., Keller, M.F., Kamboh, M.I., Kooperberg, C., Kritchevsky, S.B., LaCroix, A., Liu, K., Liu, Y., Musunuru, K., Newman, A.B., Onland-Moret, N.C., Ordovas, J., Peter, I., Post, W., Redline, S., Reis, S.E., Saxena, R., Schreiner, P.J., Volcik, K.A., Wang, X., Yusuf, S., Zonderland, A.B., Anand, S.S., Becker, D.M., Psaty, B., Rader, D.J., Reiner, A.P., Rich, S.S., Rotter, J.I., Sale, M.M., Tsai, M.Y., Borecki, I.B., Hegele, R.A., Kathiresan, S., Nalls, M.A., Taylor, H.A. Jr., Hakonarson, H., Sivapalaratnam, S., Asselbergs, F.W., Drenos, F., Wilson, J.G., Keating, B.J., 2012. Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations. PLoS One 7, e50198.
    [13]
    ENCODE Project Consortium, 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74.
    [14]
    Finucane, H.K., Bulik-Sullivan, B., Gusev, A., Trynka, G., Reshef, Y., Loh, P.R., Anttila, V., Xu, H., Zang, C., Farh, K., Ripke, S., Day, F.R.; ReproGen Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; RACI Consortium, Purcell, S., Stahl, E., Lindstrom, S., Perry, J.R., Okada, Y., Raychaudhuri, S., Daly, M.J., Patterson, N., Neale, B.M., Price, A.L., 2015. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228-1235.
    [15]
    Franzen, O., Ermel, R., Cohain, A., Akers, N.K., Di Narzo, A., Talukdar, H.A., Foroughi-Asl, H., Giambartolomei, C., Fullard, J.F., Sukhavasi, K., Koks, S., Gan, L.M., Giannarelli, C., Kovacic, J.C., Betsholtz, C., Losic, B., Michoel, T., Hao, K., Roussos, P., Skogsberg, J., Ruusalepp, A., Schadt, E.E., Bjorkegren, J.L., 2016. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science 353, 827-830.
    [16]
    Gao, J., Wei, Y., Huang, Y., Liu, D., Liu, G., Wu, M., Wu, L., Zhang, Q., Zhang, Z., Zhang, R., Liang, C., 2005. The expression of intact and mutant human apoAI/CIII/AIV/AV gene cluster in transgenic mice. J. Biol. Chem. 280, 12559-12566.
    [17]
    Gaudet, D., Alexander, V.J., Baker, B.F., Brisson, D., Tremblay, K., Singleton, W., Geary, R.S., Hughes, S.G., Viney, N.J., Graham, M.J., Crooke, R.M., Witztum, J.L., Brunzell, J.D., Kastelein, J.J., 2015. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438-447.
    [18]
    Gomaraschi, M., Baldassarre, D., Amato, M., Eligini, S., Conca, P., Sirtori, C.R., Franceschini, G., Calabresi, L., 2007. Normal vascular function despite low levels of high-density lipoprotein cholesterol in carriers of the apolipoprotein A-I(Milano) mutant. Circulation 116, 2165-2172.
    [19]
    Gombojav, B., Lee, S.J., Kho, M., Song, Y.M., Lee, K., Sung, J., 2016. Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians. J. Lipid Res. 57, 318-324.
    [20]
    GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)-Analysis Working Group; Statistical Methods groups-Analysis Working Group, Enhancing GTEx (eGTEx) groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site-NDRI; Biospecimen Collection Source Site-RPCI; Biospecimen Core Resource-VARI; Brain Bank Repository-University of Miami Brain Endowment Bank; Leidos Biomedical-Project Management; ELSI Study, Genome Browser Data Integration & Visualization-EBI; Genome Browser Data Integration & Visualization-UCSC Genomics Institute, University of California Santa Cruz; Lead analysts:; Laboratory, Data Analysis & Coordinating Center (LDACC), NIH program management:; Biospecimen collection:; Pathology:; eQTL manuscript working group:, Battle, A., Brown, C.D., Engelhardt, B.E., Montgomery, S.B., 2017. Genetic effects on gene expression across human tissues. Nature 550, 204-213.
    [21]
    Haase, C.L., Frikke-Schmidt, R., Nordestgaard, B.G., Tybjaerg-Hansen, A., 2012. Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. PLoS Genet. 8, e1003063.
    [22]
    Halley, P., Kadakkuzha, B.M., Faghihi, M.A., Magistri, M., Zeier, Z., Khorkova, O., Coito, C., Hsiao, J., Lawrence, M., Wahlestedt, C., 2014. Regulation of the apolipoprotein gene cluster by a long noncoding RNA. Cell Rep. 6, 222-230.
    [23]
    Han, Y., Dorajoo, R., Chang, X., Wang, L., Khor, C.C., Sim, X., Cheng, C.Y., Shi, Y., Tham, Y.C., Zhao, W., Chee, M.L., Sabanayagam, C., Chee, M.L., Tan, N., Wong, T.Y., Tai, E.S., Liu, J., Goh, D.Y.T., Yuan, J.M., Koh, W.P., van Dam, R.M., Low, A.F., Chan, M.Y., Friedlander, Y., Heng, C.K., 2017. Genome-wide association study identifies a missense variant at APOA5 for coronary artery disease in Multi-Ethnic Cohorts from Southeast Asia. Sci Rep 7, 17921.
    [24]
    Hoffmann, T.J., Theusch, E., Haldar, T., Ranatunga, D.K., Jorgenson, E., Medina, M.W., Kvale, M.N., Kwok, P.Y., Schaefer, C., Krauss, R.M., Iribarren, C., Risch, N., 2018. A large electronic-health-record-based genome-wide study of serum lipids. Nat. Genet. 50, 401-413.
    [25]
    Hovingh, G.K., Brownlie, A., Bisoendial, R.J., Dube, M.P., Levels, J.H., Petersen, W., Dullaart, R.P., Stroes, E.S., Zwinderman, A.H., de Groot, E., Hayden, M.R., Kuivenhoven, J.A., Kastelein, J.J., 2004. A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease. J. Am. Coll. Cardiol. 44, 1429-1435.
    [26]
    Jansen, R., Hottenga, J.J., Nivard, M.G., Abdellaoui, A., Laport, B., de Geus, E.J., Wright, F.A., Penninx, B.W.J.H., Boomsma, D.I., 2017. Conditional eQTL analysis reveals allelic heterogeneity of gene expression. Hum. Mol. Genet. 26, 1444-1451.
    [27]
    Joergensen, A.B., Frikke-Schmidt, R., Nordestgaard, B.G., Tybjaerg-Hansen, A., 2014. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32-41.
    [28]
    Kanai, M., Akiyama, M., Takahashi, A., Matoba, N., Momozawa, Y., Ikeda, M., Iwata, N., Ikegawa, S., Hirata, M., Matsuda, K., Kubo, M., Okada, Y., Kamatani, Y., 2018. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390-400.
    [29]
    Khera, A.V., Kathiresan, S., 2017. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat. Rev. Genet. 18, 331-344.
    [30]
    Khetarpal, S.A., Zeng, X., Millar, J.S., Vitali, C., Somasundara, A.V.H., Zanoni, P., Landro, J.A., Barucci, N., Zavadoski, W.J., Sun, Z., de Haard, H., Toth, I.V., Peloso, G.M., Natarajan, P., Cuchel, M., Lund-Katz, S., Phillips, M.C., Tall, A.R., Kathiresan, S., DaSilva-Jardine, P., Yates, N.A., Rader, D.J., 2017. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat. Med. 23, 1086-1094.
    [31]
    Kichaev, G., Yang, W.Y., Lindstrom, S., Hormozdiari, F., Eskin, E., Price, A.L., Kraft, P., Pasaniuc, B., 2014. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 10, e1004722.
    [32]
    Kichaev, G., Pasaniuc, B., 2015. Leveraging Functional-Annotation Data in Trans-ethnic Fine-Mapping Studies. Am. J. Hum. Genet. 97, 260-271.
    [33]
    Kichaev, G., Roytman, M., Johnson, R., Eskin, E., Lindstrom, S., Kraft, P., Pasaniuc, B., 2017. Improved methods for multi-trait fine mapping of pleiotropic risk loci. Bioinformatics 33, 248-255.
    [34]
    Klarin, D., Damrauer, S.M., Cho, K., Sun, Y.V., Teslovich, T.M., Honerlaw, J., Gagnon, D.R., DuVall, S.L., Li, J., Peloso, G.M., Chaffin, M., Small, A.M., Huang, J., Tang, H., Lynch, J.A., Ho, Y.L., Liu, D.J., Emdin, C.A., Li, A.H., Huffman, J.E., Lee, J.S., Natarajan, P., Chowdhury, R., Saleheen, D., Vujkovic, M., Baras, A., Pyarajan, S., Di Angelantonio, E., Neale, B.M., Naheed, A., Khera, A.V., Danesh, J., Chang, K.M., Abecasis, G., Willer, C., Dewey, F.E., Carey, D.J.; Global Lipids Genetics Consortium; Myocardial Infarction Genetics (MIGen) Consortium; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program, Concato, J., Gaziano, J.M., O'Donnell, C.J., Tsao, P.S., Kathiresan, S., Rader, D.J., Wilson, P.W.F., Assimes, T.L., 2018. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat. Genet. 50, 1514-1523.
    [35]
    Ko, A., Cantor, R.M., Weissglas-Volkov, D., Nikkola, E., Reddy, P.M., Sinsheimer, J.S., Pasaniuc, B., Brown, R., Alvarez, M., Rodriguez, A., Rodriguez-Guillen, R., Bautista, I.C., Arellano-Campos, O., Munoz-Hernandez, L.L., Salomaa, V., Kaprio, J., Jula, A., Jauhiainen, M., Heliovaara, M., Raitakari, O., Lehtimaki, T., Eriksson, J.G., Perola, M., Lohmueller, K.E., Matikainen, N., Taskinen, M.R., Rodriguez-Torres, M., Riba, L., Tusie-Luna, T., Aguilar-Salinas, C.A., Pajukanta, P., 2014. Amerindian-specific regions under positive selection harbour new lipid variants in Latinos. Nat. Commun. 5, 3983.
    [36]
    Kraja, A.T., Vaidya, D., Pankow, J.S., Goodarzi, M.O., Assimes, T.L., Kullo, I.J., Sovio, U., Mathias, R.A., Sun, Y.V., Franceschini, N., Absher, D., Li, G., Zhang, Q., Feitosa, M.F., Glazer, N.L., Haritunians, T., Hartikainen, A.L., Knowles, J.W., North, K.E., Iribarren, C., Kral, B., Yanek, L., O'Reilly, P.F., McCarthy, M.I., Jaquish, C., Couper, D.J., Chakravarti, A., Psaty, B.M., Becker, L.C., Province, M.A., Boerwinkle, E., Quertermous, T., Palotie, L., Jarvelin, M.R., Becker, D.M., Kardia, S.L., Rotter, J.I., Chen, Y.D., Borecki, I.B., 2011. A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. Diabetes 60, 1329-1339.
    [37]
    Lee, J.Y., Lee, B.S., Shin, D.J., Woo Park, K., Shin, Y.A., Joong Kim, K., Heo L., Young Lee, J., Kyoung Kim, Y., Jin Kim, Y., Bum Hong, C., Lee, S.H., Yoon, D., Jung Ku, H., Oh, I.Y., Kim, B.J., Lee, J., Park, S.J., Kim, J., Kawk, H.K., Lee, J.E., Park, H.K., Lee, J.E., Nam, H.Y., Park, H.Y., Shin, C., Yokota, M., Asano, H., Nakatochi, M., Matsubara, T., Kitajima, H., Yamamoto, K., Kim, H.L., Han, B.G., Cho, M.C., Jang, Y., Kim, H.S., Euy Park, J., Lee, J.Y., 2013. A genome-wide association study of a coronary artery disease risk variant. J. Hum. Genet. 58, 120-126.
    [38]
    Lee, S., Abecasis, G.R., Boehnke, M., Lin, X., 2014. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5-23.
    [39]
    Li, H., Durbin, R., 2009. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754-1760.
    [40]
    Li, Y., Kellis, M., 2016. Joint Bayesian inference of risk variants and tissue-specific epigenomic enrichments across multiple complex human diseases. Nucleic Acids Res. 44, e144.
    [41]
    Li, Y.J., Wei, Y.S., Fu, X.H., Hao, D.L., Xue, Z., Gong, H., Zhang, Z.Q., Liu, D.P., Liang, C.C., 2008. The apolipoprotein CIII enhancer regulates both extensive histone modification and intergenic transcription of human apolipoprotein AI/CIII/AIV genes but not apolipoprotein AV. J. Biol. Chem. 283, 28436-28444.
    [42]
    Libby, P., Ridker, P.M., Hansson, G.K., 2011. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317-325.
    [43]
    Liu, D.J., Peloso, G.M., Yu, H., Butterworth, A.S., Wang, X., Mahajan, A., Saleheen, D., Emdin, C., Alam, D., Alves, A.C., Amouyel, P., Di Angelantonio, E., Arveiler, D., Assimes, T.L., Auer, P.L., Baber, U., Ballantyne, C.M., Bang, L.E., Benn, M., Bis, J.C., Boehnke, M., Boerwinkle, E., Bork-Jensen, J., Bottinger, E.P., Brandslund, I., Brown, M., Busonero, F., Caulfield, M.J., Chambers, J.C., Chasman, D.I., Chen, Y.E., Chen, Y.I., Chowdhury, R., Christensen, C., Chu, A.Y., Connell, J.M., Cucca, F., Cupples, L.A., Damrauer, S.M., Davies, G., Deary, I.J., Dedoussis, G., Denny, J.C., Dominiczak, A., Dube, M.P., Ebeling, T., Eiriksdottir, G., Esko, T., Farmaki, A.E., Feitosa, M.F., Ferrario, M., Ferrieres, J., Ford, I., Fornage, M., Franks, P.W., Frayling, T.M., Frikke-Schmidt, R., Fritsche, L.G., Frossard, P., Fuster, V., Ganesh, S.K., Gao, W., Garcia, M.E., Gieger, C., Giulianini, F., Goodarzi, M.O., Grallert, H., Grarup, N., Groop, L., Grove, M.L., Gudnason, V., Hansen, T., Harris, T.B., Hayward, C., Hirschhorn, J.N., Holmen, O.L., Huffman, J., Huo, Y., Hveem, K., Jabeen, S., Jackson, A.U., Jakobsdottir, J., Jarvelin, M.R., Jensen, G.B., Joergensen, M.E., Jukema, J.W., Justesen, J.M., Kamstrup, P.R., Kanoni, S., Karpe, F., Kee, F., Khera, A.V., Klarin, D., Koistinen, H.A., Kooner, J.S., Kooperberg, C., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T., Langenberg, C., Langsted, A., Launer, L.J., Lauritzen, T., Liewald, D.C.M., Lin, L.A., Linneberg, A., Loos, R.J.F., Lu, Y., Lu, X., Magi, R., Malarstig, A., Manichaikul, A., Manning, A.K., Mantyselka, P., Marouli, E., Masca, N.G.D., Maschio, A., Meigs, J.B., Melander, O., Metspalu, A., Morris, A.P., Morrison, A.C., Mulas, A., Muller-Nurasyid, M., Munroe, P.B., Neville, M.J., Nielsen, J.B., Nielsen, S.F., Nordestgaard, B.G., Ordovas, J.M., Mehran, R., O'Donnell, C.J., Orho-Melander, M., Molony, C.M., Muntendam, P., Padmanabhan, S., Palmer, C.N.A., Pasko, D., Patel, A.P., Pedersen, O., Perola, M., Peters, A., Pisinger, C., Pistis, G., Polasek, O., Poulter, ,N., Psaty, B.M., Rader, D.J., Rasheed, A., Rauramaa, R., Reilly, D.F., Reiner, A.P., Renstrom, F., Rich, S.S., Ridker, P.M., Rioux, J.D., Robertson, N.R., Roden, D.M., Rotter, J.I., Rudan, I., Salomaa, V., Samani, N.J., Sanna, S., Sattar, N., Schmidt, E.M., Scott, R.A., Sever, P., Sevilla, R.S., Shaffer, C.M., Sim, X., Sivapalaratnam, S., Small, K.S., Smith, A.V., Smith, B.H., Somayajula, S., Southam, L., Spector, T.D., Speliotes, E.K., Starr, J.M., Stirrups, K.E., Stitziel, N., Strauch, K., Stringham, H.M., Surendran, P., Tada, H., Tall, A.R., Tang, H., Tardif, J.C., Taylor, K.D., Trompet, S., Tsao, P.S., Tuomilehto, J., Tybjaerg-Hansen, A., van Zuydam, N.R., Varbo, A., Varga, T.V., Virtamo, J., Waldenberger, M., Wang, N., Wareham, N.J., Warren, H.R., Weeke, P.E., Weinstock, J., Wessel, J., Wilson, J.G., Wilson, P.W.F., Xu, M., Yaghootkar, H., Young, R., Zeggini, E., Zhang, H., Zheng, N.S., Zhang, W., Zhang, Y., Zhou, W., Zhou, Y., Zoledziewska, M.; Charge Diabetes Working Group; EPIC-InterAct Consortium; EPIC-CVD Consortium; GOLD Consortium; VA Million Veteran Program, Howson, J.M.M., Danesh, J., McCarthy, M.I., Cowan, C.A., Abecasis, G., Deloukas, P., Musunuru, K., Willer, C.J., Kathiresan, S., 2017. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758-1766.
    [44]
    Lloyd-Jones, L.R., Holloway, A., McRae, A., Yang, J., Small, K., Zhao, J., Zeng, B., Bakshi, A., Metspalu, A., Dermitzakis, M., Gibson, G., Spector, T., Montgomery, G., Esko, T., Visscher, P.M., Powell, J.E., 2017. The genetic architecture of gene expression in peripheral blood. Am. J. Hum. Genet. 100, 228-237.
    [45]
    Lu, X., Wang, L., Chen, S., He, L., Yang, X., Shi, Y., Cheng, J., Zhang, L., Gu, C.C., Huang, J., Wu, T., Ma, Y., Li, J., Cao, J., Chen, J., Ge, D., Fan, Z., Li, Y., Zhao, L., Li, H., Zhou, X., Chen, L., Liu, D., Chen, J., Duan, X., Hao, Y., Wang, L., Lu, F., Liu, Z., Yao, C., Shen, C., Pu, X., Yu, L., Fang, X., Xu, L., Mu, J., Wu, X., Zheng, R., Wu, N., Zhao, Q., Li, Y., Liu, X., Wang, M., Yu, D., Hu, D., Ji, X., Guo, D., Sun, D., Wang, Q., Yang, Y., Liu, F., Mao, Q., Liang, X., Ji, J., Chen, P., Mo, X., Li, D., Chai, G., Tang, Y., Li, X., Du, Z., Liu, X., Dou, C., Yang, Z., Meng, Q., Wang, D., Wang, R., Yang, J., Schunkert, H., Samani, N.J., Kathiresan, S., Reilly, M.P., Erdmann, J.; Coronary Artery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Peng, X., Wu, X., Liu, D., Yang, Y., Chen, R., Qiang, B., Gu, D., 2012. Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nat Genet 44, 890-894.
    [46]
    Lu, X., Li, J., Li, H., Chen, Y., Wang, L., He, M., Wang, Y., Sun, L., Hu, Y., Huang, J., Wang, F., Liu, X., Chen, S., Yu, K., Yang, X., Mo, Z., Lin, X., Wu, T., Gu, D., 2016. Coding-sequence variants are associated with blood lipid levels in 14,473 Chinese. Hum. Mol. Genet. 25, 4107-4116.
    [47]
    Lu, X., Peloso, G.M., Liu, D.J., Wu, Y., Zhang, H., Zhou, W., Li, J., Tang, C.S., Dorajoo, R., Li, H., Long, J., Guo, X., Xu, M., Spracklen, C.N., Chen, Y., Liu, X., Zhang, Y., Khor, C.C., Liu, J., Sun, L., Wang, L., Gao, Y.T., Hu, Y., Yu, K., Wang, Y., Cheung, C.Y.Y., Wang, F., Huang, J., Fan, Q., Cai, Q., Chen, S., Shi, J., Yang, X., Zhao, W., Sheu, W.H., Cherny, S.S., He, M., Feranil, A.B., Adair, L.S., Gordon-Larsen, P., Du, S., Varma, R., Chen, Y.I., Shu, X.O., Lam, K.S.L., Wong, T.Y., Ganesh, S.K., Mo, Z., Hveem, K., Fritsche, L.G., Nielsen, J.B., Tse, H.F., Huo, Y., Cheng, C.Y., Chen, Y.E., Zheng, W., Tai, E.S., Gao, W., Lin, X., Huang, W., Abecasis, G.; GLGC Consortium, Kathiresan, S., Mohlke, K.L., Wu, T., Sham, P.C., Gu, D., Willer, C.J., 2017. Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. Nat. Genet. 49, 1722-1730.
    [48]
    Mishiro, T., Ishihara, K., Hino, S., Tsutsumi, S., Aburatani, H., Shirahige, K., Kinoshita, Y., Nakao, M., 2009. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO. J. 28, 1234-1245.
    [49]
    Musunuru, K., Romaine, S.P., Lettre, G., Wilson, J.G., Volcik, K.A., Tsai, M.Y., Taylor, H.A. Jr., Schreiner, P.J., Rotter, J.I., Rich, S.S., Redline, S., Psaty, B.M., Papanicolaou, G.J., Ordovas, J.M., Liu, K., Krauss, R.M., Glazer, N.L., Gabriel, S.B., Fornage, M., Cupples, L.A., Buxbaum, S.G., Boerwinkle, E., Ballantyne, C.M., Kathiresan, S., Rader, D.J., 2012. Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project. PLoS One 7, e36473.
    [50]
    Musunuru, K., Kathiresan, S., 2016. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ. Res. 118, 579-585.
    [51]
    Nikpay, M., Goel, A., Won, H.H., Hall, L.M., Willenborg, C., Kanoni, S., Saleheen, D., Kyriakou, T., Nelson, C.P., Hopewell, J.C., Webb, T.R., Zeng, L., Dehghan, A., Alver, M., Armasu, S.M., Auro, K., Bjonnes, A., Chasman, D.I., Chen, S., Ford, I., Franceschini, N., Gieger, C., Grace, C., Gustafsson, S., Huang, J., Hwang, S.J., Kim, Y.K., Kleber, M.E., Lau, K.W., Lu, X., Lu, Y., Lyytikainen, L.P., Mihailov, E., Morrison, A.C., Pervjakova, N., Qu, L., Rose, L.M., Salfati, E., Saxena, R., Scholz, M., Smith, A.V., Tikkanen, E., Uitterlinden, A., Yang, X., Zhang, W., Zhao, W., de Andrade, M., de Vries, P.S., van Zuydam, N.R., Anand, S.S., Bertram, L., Beutner, F., Dedoussis, G., Frossard, P., Gauguier, D., Goodall, A.H., Gottesman, O., Haber, M., Han, B.G., Huang, J., Jalilzadeh, S., Kessler, T., Konig, I.R., Lannfelt, L., Lieb, W., Lind, L., Lindgren, C.M., Lokki, M.L., Magnusson, P.K., Mallick, N.H., Mehra, N., Meitinger, T., Memon, F.U., Morris, A.P., Nieminen, M.S., Pedersen, N.L., Peters, A., Rallidis, L.S., Rasheed, A., Samuel, M., Shah, S.H., Sinisalo, J., Stirrups, K.E., Trompet, S., Wang, L., Zaman, K.S., Ardissino, D., Boerwinkle, E., Borecki, I.B., Bottinger, E.P., Buring, J.E., Chambers, J.C., Collins, R., Cupples, L.A., Danesh, J., Demuth, I., Elosua, R., Epstein, S.E., Esko, T., Feitosa, M.F., Franco, O.H., Franzosi, M.G., Granger, C.B., Gu, D., Gudnason, V., Hall, A.S., Hamsten, A., Harris, T.B., Hazen, S.L., Hengstenberg, C., Hofman, A., Ingelsson, E., Iribarren, C., Jukema, J.W., Karhunen, P.J., Kim, B.J., Kooner, J.S., Kullo, I.J., Lehtimaki, T., Loos, R.J.F., Melander, O., Metspalu, A., Marz, W., Palmer, C.N., Perola, M., Quertermous, T., Rader, D.J., Ridker, P.M., Ripatti, S., Roberts, R., Salomaa, V., Sanghera, D.K., Schwartz, S.M., Seedorf, U., Stewart, A.F., Stott, D.J., Thiery, J., Zalloua, P.A., O'Donnell, C.J., Reilly, M.P., Assimes, T.L., Thompson, J.R., Erdmann, J., Clarke, R., Watkins, H., Kathiresan, S., McPherson, R., Deloukas, P., Schunkert, H., Samani, N.J., Farrall, M., 2015. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47, 1121-1130.
    [52]
    Nordestgaard, B.G., 2016. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circ. Res. 118, 547-563.
    [53]
    Parker, S.C., Stitzel, M.L., Taylor, D.L., Orozco, J.M., Erdos, M.R., Akiyama, J.A., van Bueren, K.L., Chines, P.S., Narisu, N.; NISC Comparative Sequencing Program, Black, B.L., Visel, A., Pennacchio, L.A., Collins, F.S.; National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors; NISC Comparative Sequencing Program Authors., 2013. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl. Acad. Sci. U. S. A. 110, 17921-17926.
    [54]
    Pickrell, J.K., 2014. Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am. J. Hum. Genet. 94, 559-573.
    [55]
    Pollin, T.I., Damcott, C.M., Shen, H., Ott, S.H., Shelton, J., Horenstein, R.B., Post, W., McLenithan, J.C., Bielak, L.F., Peyser, P.A., Mitchell, B.D., Miller, M., O'Connell, J.R., Shuldiner, A.R., 2008. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322, 1702-1705.
    [56]
    Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J., Sham, P.C., 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575.
    [57]
    Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., Ziller, M.J., Amin, V., Whitaker, J.W., Schultz, M.D., Ward, L.D., Sarkar, A., Quon, G., Sandstrom, R.S., Eaton, M.L., Wu, Y.C., Pfenning, A.R., Wang, X., Claussnitzer, M., Liu, Y., Coarfa, C., Harris, R.A., Shoresh, N., Epstein, C.B., Gjoneska, E., Leung, D., Xie, W., Hawkins, R.D., Lister, R., Hong, C., Gascard, P., Mungall, A.J., Moore, R., Chuah, E., Tam, A., Canfield, T.K., Hansen, R.S., Kaul, R., Sabo, P.J., Bansal, M.S., Carles, A., Dixon, J.R., Farh, K.H., Feizi, S., Karlic, R., Kim, A.R., Kulkarni, A., Li, D., Lowdon, R., Elliott, G., Mercer, T.R., Neph, S.J., Onuchic, V., Polak, P., Rajagopal, N., Ray, P., Sallari, R.C., Siebenthall, K.T., Sinnott-Armstrong, N.A., Stevens, M., Thurman, R.E., Wu, J., Zhang, B., Zhou, X., Beaudet, A.E., Boyer, L.A., De Jager, P.L., Farnham, P.J., Fisher, S.J., Haussler, D., Jones, S.J., Li, W., Marra, M.A., McManus, M.T., Sunyaev, S., Thomson, J.A., Tlsty, T.D., Tsai, L.H., Wang, W., Waterland, R.A., Zhang, M.Q., Chadwick, L.H., Bernstein, B.E., Costello, J.F., Ecker, J.R., Hirst, M., Meissner, A., Milosavljevic, A., Ren, B., Stamatoyannopoulos, J.A., Wang, T., Kellis, M., 2015. Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330.
    [58]
    Schunkert, H., Konig, I.R., Kathiresan, S., Reilly, M.P., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S.S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, D.M., Becker, L.C., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Braund, P.S., Brown, M.J., Burnett, M.S., Buysschaert, I.; Cardiogenics, Carlquist, J.F., Chen, L., Cichon, S., Codd, V., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J.M., Diemert, P., Do, R., Doering, A., Eifert, S., Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S.E., de Faire, U., Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Kastelein, J.J., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Lettre, G., Li, M., Lieb, W., Loley, C., Lotery, A.J., Mannucci, P.M., Maouche, S., Martinelli, N., McKeown, P.P., Meisinger, C., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen, T.W., Muhlestein, J.B., Munzel, T., Musunuru, K., Nahrstaedt, J., Nelson, C.P., Nothen, M.M., Olivieri, O., Patel, R.S., Patterson, C.C., Peters, A., Peyvandi, F., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Rosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A., Smith, T.B., Snoep, J.D., Soranzo, N., Spertus, J.A., Stark, K., Stirrups, K., Stoll, M., Tang, W.H., Tennstedt, S., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., van Rij, A.M., Voight, B.F., Wareham, N.J., Wells, G.A., Wichmann, H.E., Wild, P.S., Willenborg, C., Witteman, J.C., Wright, B.J., Ye, S., Zeller, T., Ziegler, A., Cambien, F., Goodall, A.H., Cupples, L.A., Quertermous, T., Marz, W., Hengstenberg, C., Blankenberg, S., Ouwehand, W.H., Hall, A.S., Deloukas, P., Thompson, J.R., Stefansson, K., Roberts, R., Thorsteinsdottir, U., O'Donnell, C.J., McPherson, R., Erdmann, J.; CARDIoGRAM Consortium, Samani, N.J., 2011. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333-338.
    [59]
    Shou, W., Wang, Y., Xie, F., Wang, B., Yang, L., Wu, H., Wang, Y., Wang, Z., Shi, J., Huang, W., 2014. A functional polymorphism affecting the APOA5 gene expression is causally associated with plasma triglyceride levels conferring coronary atherosclerosis risk in Han Chinese Population. Biochim. Biophys. Acta. 1842, 2147-2154.
    [60]
    Tak, Y.G., Farnham, P.J., 2015. Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome. Epigenetics Chromatin. 8, 57.
    [61]
    Takeuchi, F., Yokota, M., Yamamoto, K., Nakashima, E., Katsuya, T., Asano, H., Isono, M., Nabika, T., Sugiyama, T., Fujioka, A., Awata, N., Ohnaka, K., Nakatochi, M., Kitajima, H., Rakugi, H., Nakamura, J., Ohkubo, T., Imai, Y., Shimamoto, K., Yamori, Y., Yamaguchi, S., Kobayashi, S., Takayanagi, R., Ogihara, T., Kato, N., 2012. Genome-wide association study of coronary artery disease in the Japanese. Eur. J. Hum. Genet. 20, 333-340.
    [62]
    Talmud, P.J., Drenos, F., Shah. S., Shah, T., Palmen, J., Verzilli, C., Gaunt, T.R., Pallas, J., Lovering, R., Li, K., Casas, J.P., Sofat, R., Kumari, M., Rodriguez, S., Johnson, T., Newhouse, S.J., Dominiczak, A., Samani, N.J., Caulfield, M., Sever, P., Stanton, A., Shields, D.C., Padmanabhan, S., Melander, O., Hastie, C., Delles, C., Ebrahim, S., Marmot, M.G., Smith, G.D., Lawlor, D.A., Munroe, P.B., Day, I.N., Kivimaki, M., Whittaker, J., Humphries, S.E., Hingorani, A.D.; ASCOT investigators; NORDIL investigators; BRIGHT Consortium., 2009. Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Am. J. Hum. Genet. 85, 628-642.
    [63]
    Teslovich, T.M., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Ripatti, S., Chasman, D.I., Willer, C.J., Johansen, C.T., Fouchier, S.W., Isaacs, A., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Aulchenko, Y.S., Thorleifsson, G., Feitosa, M.F., Chambers, J., Orho-Melander, M., Melander, O., Johnson, T., Li, X., Guo, X., Li, M., Shin Cho, Y., Jin Go, M., Jin Kim, Y., Lee, J.Y., Park, T., Kim, K., Sim, X., Twee-Hee Ong, R., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Song, K., Hua Zhao, J., Yuan, X., Luan, J., Lamina, C., Ziegler, A., Zhang, W., Zee, R.Y., Wright, A.F., Witteman, J.C., Wilson, J.F., Willemsen, G., Wichmann, H.E., Whitfield, J.B., Waterworth, D.M., Wareham, N.J., Waeber, G., Vollenweider, P., Voight, B.F., Vitart, V., Uitterlinden, A.G., Uda, M., Tuomilehto, J., Thompson, J.R., Tanaka, T., Surakka, I., Stringham, H.M., Spector, T.D., Soranzo, N., Smit, J.H., Sinisalo, J., Silander, K., Sijbrands, E.J., Scuteri, A., Scott, J., Schlessinger, D., Sanna, S., Salomaa, V., Saharinen, J., Sabatti, C., Ruokonen, A., Rudan, I., Rose, L.M., Roberts, R., Rieder, M., Psaty, B.M., Pramstaller, P.P., Pichler, I., Perola, M., Penninx, B.W., Pedersen, N.L., Pattaro, C., Parker, A.N., Pare, G., Oostra, B.A., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., Meitinger, T., McPherson, R., McCarthy, M.I., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Mangino, M., Magnusson, P.K., Lucas, G., Luben, R., Loos, R.J., Lokki, M.L., Lettre, G., Langenberg, C., Launer, L.J., Lakatta, E.G., Laaksonen, R., Kyvik, K.O., Kronenberg, F., Konig, I.R., Khaw, K.T., Kaprio, J., Kaplan, L.M., Johansson, A., Jarvelin, M.R., Janssens, A.C., Ingelsson, E., Igl, W., Kees, Hovingh, G., Hottenga, J.J., Hofman, A., Hicks, A.A., Hengstenberg, C., Heid, I.M., Hayward, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Gyllensten, U., Guiducci, C., Groop, L.C., Gonzalez, E., Gieger, C., Freimer, N.B., Ferrucci, L., Erdmann, J., Elliott, P., Ejebe, K.G., Doring, A., Dominiczak, A.F., Demissie, S., Deloukas, P., de Geus, E.J., de Faire, U., Crawford, G., Collins, F.S., Chen, Y.D., Caulfield, M.J., Campbell, H., Burtt, N.P., Bonnycastle, L.L., Boomsma, D.I., Boekholdt, S.M., Bergman, R.N., Barroso, I., Bandinelli, S., Ballantyne, C.M., Assimes, T.L., Quertermous, T., Altshuler, D., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Adair, L.S., Taylor, H.A. Jr., Borecki, I.B., Gabriel, S.B., Wilson, J.G., Holm, H., Thorsteinsdottir, U., Gudnason, V., Krauss, R.M., Mohlke, K.L., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Rotter, J.I., Boerwinkle, E., Strachan, D.P., Mooser, V., Stefansson, K., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., van Duijn, C.M., Peltonen, L., Abecasis, G.R., Boehnke, M., Kathiresan, S., 2010. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707-713.
    [64]
    Timpson, N.J., Walter, K., Min, J.L., Tachmazidou, I., Malerba, G., Shin, S.Y., Chen, L., Futema, M., Southam, L., Iotchkova, V., Cocca, M., Huang, J., Memari, Y., McCarthy, S., Danecek, P., Muddyman, D., Mangino, M., Menni, C., Perry, J.R., Ring, S.M., Gaye, A., Dedoussis, G., Farmaki, A.E., Burton, P., Talmud, P.J., Gambaro, G., Spector, T.D., Smith, G.D., Durbin, R., Richards, J.B., Humphries, S.E., Zeggini, E., Soranzo, N.; UK1OK Consortium Members; UK1OK Consortium Members, 2014. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nat. Commun. 5, 4871.
    [65]
    Van der Auwera, G.A., Carneiro, M.O., Hartl, C., Poplin, R., Del Angel, G., Levy-Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., Banks, E., Garimella, K.V., Altshuler, D., Gabriel, S., DePristo, M.A., 2013. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 11.10.1-33.
    [66]
    Wang, F., Xu, C.Q., He, Q., Cai, J.P., Li, X.C., Wang, D., Xiong, X., Liao, Y.H., Zeng, Q.T., Yang, Y.Z., Cheng, X., Li, C., Yang, R., Wang, C.C., Wu, G., Lu, Q.L., Bai, Y., Huang, Y.F., Yin, D., Yang, Q., Wang, X.J., Dai, D.P., Zhang, R.F., Wan, J., Ren, J.H., Li, S.S., Zhao, Y.Y., Fu, F.F., Huang, Y., Li, Q.X., Shi, S.W., Lin, N., Pan, Z.W., Li, Y., Yu, B., Wu, Y.X., Ke, Y.H., Lei, J., Wang, N., Luo, C.Y., Ji, L.Y., Gao, L.J., Li, L., Liu, H., Huang, E.W., Cui, J., Jia, N., Ren, X., Li, H., Ke, T., Zhang, X.Q., Liu, J.Y., Liu, M.G., Xia, H., Yang, B., Shi, L.S., Xia, Y.L., Tu, X., Wang, Q.K., 2011. Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat. Genet. 43, 345-349.
    [67]
    Willer, C.J., Schmidt, E.M., Sengupta, S., Peloso, G.M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M.L., Mora, S., Beckmann, J.S., Bragg-Gresham, J.L., Chang, H.Y., Demirkan, A., Den Hertog, H.M., Do, R., Donnelly, L.A., Ehret, G.B., Esko, T., Feitosa, M.F., Ferreira, T., Fischer, K., Fontanillas, P., Fraser, R.M., Freitag, D.F., Gurdasani, D., Heikkila, K., Hypponen, E., Isaacs, A., Jackson, A.U., Johansson, A., Johnson, T., Kaakinen, M., Kettunen, J., Kleber, M.E., Li, X., Luan, J., Lyytikainen, L.P., Magnusson, P.K.E., Mangino, M., Mihailov, E., Montasser, M.E., Muller-Nurasyid, M., Nolte, I.M., O'Connell, J.R., Palmer, C.D., Perola, M., Petersen, A.K., Sanna, S., Saxena, R., Service, S.K., Shah, S., Shungin, D., Sidore, C., Song, C., Strawbridge, R.J., Surakka, I., Tanaka, T., Teslovich, T.M., Thorleifsson, G., Van den Herik, E.G., Voight, B.F., Volcik, K.A., Waite, L.L., Wong, A., Wu, Y., Zhang, W., Absher, D., Asiki, G., Barroso, I., Been, L.F., Bolton, J.L., Bonnycastle, L.L., Brambilla, P., Burnett, M.S., Cesana, G., Dimitriou, M., Doney, A.S.F., Doring, A., Elliott, P., Epstein, S.E., Ingi Eyjolfsson, G., Gigante, B., Goodarzi, M.O., Grallert, H., Gravito, M.L., Groves, C.J., Hallmans, G., Hartikainen, A.L., Hayward, C., Hernandez, D., Hicks, A.A., Holm, H., Hung, Y.J., Illig, T., Jones, M.R., Kaleebu, P., Kastelein, J.J.P., Khaw, K.T., Kim, E., Klopp, N., Komulainen, P., Kumari, M., Langenberg, C., Lehtimaki, T., Lin, S.Y., Lindstrom, J., Loos, R.J.F., Mach, F., McArdle, W.L., Meisinger, C., Mitchell, B.D., Muller, G., Nagaraja, R., Narisu, N., Nieminen, T.V.M., Nsubuga, R.N., Olafsson, I., Ong, K.K., Palotie, A., Papamarkou, T., Pomilla, C., Pouta, A., Rader, D.J., Reilly, M.P., Ridker, P.M., Rivadeneira, F., Rudan, I., Ruokonen, A., Samani, N., Scharnagl, H., Seeley, J., Silander, K., Stancakova, A., Stirrups, K., Swift, A.J., Tiret, L., Uitterlinden, A.G., van Pelt, L.J., Vedantam, S., Wainwright, N., Wijmenga, C., Wild, S.H., Willemsen, G., Wilsgaard, T., Wilson, J.F., Young, E.H., Zhao, J.H., Adair, L.S., Arveiler, D., Assimes, T.L., Bandinelli, S., Bennett, F., Bochud, M., Boehm, B.O., Boomsma, D.I., Borecki, I.B., Bornstein, S.R., Bovet, P., Burnier, M., Campbell, H., Chakravarti, A., Chambers, J.C., Chen, Y.I., Collins, F.S., Cooper, R.S., Danesh, J., Dedoussis, G., de Faire, U., Feranil, A.B., Ferrieres, J., Ferrucci, L., Freimer, N.B., Gieger, C., Groop, L.C., Gudnason, V., Gyllensten, U., Hamsten, A., Harris, T.B., Hingorani, A., Hirschhorn, J.N., Hofman, A., Hovingh, G.K., Hsiung, C.A., Humphries, S.E., Hunt, S.C., Hveem, K., Iribarren, C., Jarvelin, M.R., Jula, A., Kahonen, M., Kaprio, J., Kesaniemi, A., Kivimaki, M., Kooner, J.S., Koudstaal, P.J., Krauss, R.M., Kuh, D., Kuusisto, J., Kyvik, K.O., Laakso, M., Lakka, T.A., Lind, L., Lindgren, C.M., Martin, N.G., Marz, W., McCarthy, M.I., McKenzie, C.A., Meneton, P., Metspalu, A., Moilanen, L., Morris, A.D., Munroe, P.B., Njoelstad, I., Pedersen, N.L., Power, C., Pramstaller, P.P., Price, J.F., Psaty, B.M., Quertermous, T., Rauramaa, R., Saleheen, D., Salomaa, V., Sanghera, D.K., Saramies, J., Schwarz, P.E.H., Sheu, W.H., Shuldiner, A.R., Siegbahn, A., Spector, T.D., Stefansson, K., Strachan, D.P., Tayo, B.O., Tremoli, E., Tuomilehto, J., Uusitupa, M., van Duijn, C.M., Vollenweider, P., Wallentin, L., Wareham, N.J., Whitfield, J.B., Wolffenbuttel, B.H.R., Ordovas, J.M., Boerwinkle, E., Palmer, C.N.A., Thorsteinsdottir, U., Chasman, D.I., Rotter, J.I., Franks, P.W., Ripatti, S., Cupples, L.A., Sandhu, M.S., Rich, S.S., Boehnke, M., Deloukas, P., Kathiresan, S., Mohlke, K.L., Ingelsson, E., Abecasis, G.R.; Global Lipids Genetics Consortium, 2013. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274-1283.
    [68]
    Yang, J., Lee, S.H., Goddard, M.E., Visscher, PM., 2011. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76-82.
    [69]
    Yang, J., Ferreira, T., Morris, A.P., Medland, S.E.; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Madden, P.A., Heath, A.C., Martin, N.G., Montgomery, G.W., Weedon, M.N., Loos, R.J., Frayling, T.M., McCarthy, M.I., Hirschhorn, J.N., Goddard, M.E., Visscher, P.M., 2012. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369-375, S1-S3.
    [70]
    Zhan, X., Hu, Y., Li, B., Abecasis, G.R., Liu, D.J., 2016 RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data. Bioinformatics 32, 1423-1426.
    [71]
    Zhernakova, D.V., Deelen, P., Vermaat, M., van Iterson, M., van Galen, M., Arindrarto, W., van 't Hof, P., Mei, H., van Dijk, F., Westra, H.J., Bonder, M.J., van Rooij, J., Verkerk, M., Jhamai, P.M., Moed, M., Kielbasa, S.M., Bot, J., Nooren, I., Pool, R., van Dongen, J., Hottenga, J.J., Stehouwer, C.D., van der Kallen, C.J., Schalkwijk, C.G., Zhernakova, A., Li, Y., Tigchelaar, E.F., de Klein, N., Beekman, M., Deelen, J., van Heemst, D., van den Berg, L.H., Hofman, A., Uitterlinden, A.G., van Greevenbroek, M.M., Veldink, J.H., Boomsma, D.I., van Duijn, C.M., Wijmenga, C., Slagboom, P.E., Swertz, M.A., Isaacs, A., van Meurs, J.B., Jansen, R., Heijmans, B.T., 't Hoen, P.A., Franke, L., 2017. Identification of context-dependent expression quantitative trait loci in whole blood. Nat. Genet. 49, 139-145.
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