Association of exome sequences with plasma C-reactive protein levels in >9000 participants

Human Molecular Genetics

Volumn 24, Issue 2, 2015, Pages 559-571

  Schick, Ursula M ^a   Auer, Paul L ^a,b   Bis, Joshua C ^c   Lin, Honghuang ^d   Wei, Peng ^e   Pankratz, Nathan ^g   Lange, Leslie A ^h   Brody, Jennifer ^c   Stitziel, Nathan O ^i,j   Kim, Daniel S ^k   Carlson, Christopher S ^a   Fornage, Myriam ^e,f   Haessler, Jeffery ^a   Hsu, Li ^a,k   Jackson, Rebecca D ^l   Kooperberg, Charles ^a   Leal, Suzanne M ^m   Psaty, Bruce M ^c,k,o   Boerwinkle, Eric ^e,n   Tracy, Russell ^p   Ardissino, Diego ^q   Shah, Svati ^r   Willer, Cristen ^s,t   Loos, Ruth ^u   Melander, Olle ^v   Mcpherson, Ruth ^w   Hovingh, Kees ^x   Reilly, Muredach ^y   Watkins, Hugh ^z,aa   Girelli, Domenico ^ab   Fontanillas, Pierre ^ac   Chasman, Daniel I ^ad   Gabriel, Stacey B ^ac   Gibbs, Richard ⁿ   Nickerson, Deborah A ^k   Kathiresan, Sekar ^ac,ae   Peters, Ulrike ^a   Dupuis, Josée ^af,ag   Wilson, James G ^ah   Rich, Stephen S ^ai   Morrison, Alanna C ^e   Benjamin, Emelia J ^d,af,ag   Gross, Myron D ^g   Reiner, Alex P ^a,k   more..

^a Fred Hutchinson Cancer Research Center   (United States)

^b UNIVERSITY OF WISCONSIN MILWAUKEE   (United States)

^c UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^d BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF TEXAS SCHOOL OF PUBLIC HEALTH   (United States)

^f UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^g UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^h UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

ⁱ Cardiovascular Division   (United States)

^j WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^k UNIVERSITY OF WASHINGTON   (United States)

^l OHIO STATE UNIVERSITY   (United States)

^m Baylor College of Medicine ^*  (United States)

ⁿ BAYLOR COLLEGE OF MEDICINE   (United States)

^o CENTER FOR HEALTH STUDIES   (United States)

^p UNIVERSITY OF VERMONT   (United States)

^q UNIVERSITY HOSPITAL OF PARMA   (Italy)

^r DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^s Division of Cardiovascular Medicine   (United States)

^t UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^u MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^v LUND UNIVERSITY   (Sweden)

^w UNIVERSITY OF OTTAWA HEART INSTITUTE   (Canada)

^x ACADEMIC MEDICAL CENTER   (Netherlands)

^y UNIVERSITY OF PENNSYLVANIA   (United States)

^z UNIVERSITY OF OXFORD   (United Kingdom)

^aa UNIVERSITY OF OXFORD   (United Kingdom)

^ab UNIVERSITY OF VERONA   (Italy)

^ac BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^ad BRIGHAM AND WOMEN S HOSPITAL   (United States)

^ae HARVARD MEDICAL SCHOOL   (United States)

^af FRAMINGHAM HEART STUDY   (United States)

^ag BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH   (United States)

^ah UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^ai UNIVERSITY OF VIRGINIA   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN E2; C REACTIVE PROTEIN; HEPATOCYTE NUCLEAR FACTOR 1; INTERLEUKIN 6 RECEPTOR; LEPTIN RECEPTOR; MEMBRANE PROTEIN; METHIONINE; RETINOIC ACID RECEPTOR ALPHA; THREONINE; TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 40; UNCLASSIFIED DRUG; HEPATOCYTE NUCLEAR FACTOR 1ALPHA; HNF1A PROTEIN, HUMAN; IL6R PROTEIN, HUMAN;

ADULT; AFRICAN AMERICAN; AMINO ACID SUBSTITUTION; ARTICLE; CHROMOSOME 19Q; CRP GENE; EUROPEAN AMERICAN; EXOME; FEMALE; GENE; GENE FREQUENCY; GENE LOCUS; GENETIC ASSOCIATION; GENETIC VARIABILITY; HNF1A GENE; HUMAN; IL6R GENE; INFLAMMATION; ISCHEMIC HEART DISEASE; MAJOR CLINICAL STUDY; MALE; PHENOTYPE; PRIORITY JOURNAL; RORA GENE; SEQUENCE ANALYSIS; SINGLE NUCLEOTIDE POLYMORPHISM; TOMM40 GENE; YOUNG ADULT; BLOOD; CARDIOVASCULAR DISEASE; CAUCASIAN; CHEMISTRY; COHORT ANALYSIS; GENETIC PREDISPOSITION; GENETICS; METABOLISM; PLASMA; RISK FACTOR;

ADULT; AFRICAN AMERICANS; C-REACTIVE PROTEIN; CARDIOVASCULAR DISEASES; COHORT STUDIES; EUROPEAN CONTINENTAL ANCESTRY GROUP; EXOME; FEMALE; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HEPATOCYTE NUCLEAR FACTOR 1-ALPHA; HUMANS; MALE; PLASMA; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, INTERLEUKIN-6; RISK FACTORS;

EID: 84922454111     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddu450     Document Type: Article

References (87)

1. Dehghan, A., Kardys, I., de Maat, M.P., Uitterlinden, A.G., Sijbrands, E.J., Bootsma, A.H., Stijnen, T., Hofman, A., Schram, M.T. and Witteman, J.C. (2007) Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes, 56, 872-878.
2. Ridker, P.M. (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation, 107, 363-369.
3. Sesso, H.D., Buring, J.E., Rifai, N., Blake, G.J., Gaziano, J.M. and Ridker, P.M. (2003) C-reactive protein and the risk of developing hypertension. J. Am. Med. Assoc., 290, 2945-2951.
4. Erlinger, T.P., Platz, E.A., Rifai, N. and Helzlsouer, K.J. (2004) C-reactive protein and the risk of incident colorectal cancer. J. Am. Med. Assoc., 291, 585-590.
5. Kaptoge, S., Di Angelantonio, E., Lowe, G., Pepys, M.B., Thompson, S.G., Collins, R. and Danesh, J. (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet, 375, 132-140.
6. Ridker, P.M., Hennekens, C.H., Buring, J.E. and Rifai, N. (2000) C-reactive proteinand other markers ofinflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med., 342, 836-843.
7. Ridker, P.M., Rifai, N., Rose, L., Buring, J.E. and Cook, N.R. (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med., 347, 1557-1565.
8. Tracy, R.P., Lemaitre, R.N., Psaty, B.M., Ives, D.G., Evans, R.W., Cushman, M., Meilahn, E.N. and Kuller, L.H. (1997) Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler. Thromb. Vasc. Biol., 17, 1121-1127.
9. Miller, M., Zhan, M. and Havas, S. (2005) High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors: the Third National Health and Nutrition Examination Survey. Arch. Intern. Med., 165, 2063-2068.
10. Greenland, P., Alpert, J.S., Beller, G.A., Benjamin, E.J., Budoff, M.J., Fayad, Z.A., Foster, E., Hlatky, M.A., Hodgson, J.M., Kushner, F.G. et al. (2010) 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 122, 2748-2764.
11. Kardys, I., de Maat, M.P., Uitterlinden, A.G., Hofman, A. and Witteman, J.C. (2006) C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam Study. Eur. Heart J., 27, 1331-1337.
12. Lange, L.A., Carlson, C.S., Hindorff, L.A., Lange, E.M., Walston, J., Durda, J.P., Cushman, M., Bis, J.C., Zeng, D., Lin, D. et al. (2006) Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. J. Am. Med. Assoc., 296, 2703-2711.
13. Casas, J.P., Shah, T., Cooper, J., Hawe, E., McMahon, A.D., Gaffney, D., Packard, C.J., O'Reilly, D.S., Juhan-Vague, I., Yudkin, J.S. et al. (2006) Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int. J. Epidemiol., 35, 922-931.
14. Pai, J.K., Mukamal, K.J., Rexrode, K.M. and Rimm, E.B. (2008) C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies. PLoS ONE, 3, e1395.
15. Lawlor, D.A., Harbord, R.M., Timpson, N.J., Lowe, G.D., Rumley, A., Gaunt, T.R., Baker, I., Yarnell, J.W., Kivimaki, M., Kumari, M. et al. (2008) The association of C-reactive protein and CRPgenotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants. PLoS ONE, 3, e3011.
16. Zacho, J., Tybjaerg-Hansen, A., Jensen, J.S., Grande, P., Sillesen, H. and Nordestgaard, B.G. (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med., 359, 1897-1908.
17. Elliott, P., Chambers, J.C., Zhang, W., Clarke, R., Hopewell, J.C., Peden, J.F., Erdmann, J., Braund, P., Engert, J.C., Bennett, D. et al. (2009) Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. J. Am. Med. Assoc., 302, 37-48.
18. Dehghan, A., Dupuis, J., Barbalic, M., Bis, J.C., Eiriksdottir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P. et al. (2011) Meta-analysis of genome-wide association studies in .80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation, 123, 731-738.
19. Reiner, A.P., Barber, M.J., Guan, Y., Ridker, P.M., Lange, L.A., Chasman, D.I., Walston, J.D., Cooper, G.M., Jenny, N.S., Rieder, M.J. et al. (2008) Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am. J. Hum. Genet., 82, 1193-1201.
20. Ridker, P.M., Pare, G., Parker, A., Zee, R.Y., Danik, J.S., Buring, J.E., Kwiatkowski, D., Cook, N.R., Miletich, J.P. and Chasman, D.I. (2008) Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am. J. Hum. Genet., 82, 1185-1192.
21. Sabatti, C., Service, S.K., Hartikainen, A.L., Pouta, A., Ripatti, S., Brodsky, J., Jones, C.G., Zaitlen, N.A., Varilo, T., Kaakinen, M. et al. (2009) Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat. Genet., 41, 35-46.
22. Benjamin, E.J., Dupuis, J., Larson, M.G., Lunetta, K.L., Booth, S.L., Govindaraju, D.R., Kathiresan, S., Keaney, J.F. Jr, Keyes, M.J., Lin, J.P. et al. (2007) Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC Med. Genet., 8 (Suppl 1), S11.
23. Wu, Y., McDade, T.W., Kuzawa, C.W., Borja, J., Li, Y., Adair, L.S., Mohlke, K.L. and Lange, L.A. (2012) Genome-wide association with C-reactive protein levels in CLHNS: evidence for the CRP and HNF1A loci and their interaction with exposure to a pathogenic environment. Inflammation, 35, 574-583.
24. Okada, Y., Takahashi, A., Ohmiya, H., Kumasaka, N., Kamatani, Y., Hosono, N., Tsunoda, T., Matsuda, K., Tanaka, T., Kubo, M. et al. (2011) Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. Hum. Mol. Genet., 20, 1224-1231.
25. Kong, M. and Lee, C. (2013) Genetic associations with C-reactive protein level and white blood cell count in the KARE study. Int. J. Immunogenet., 40, 120-125.
26. Reiner, A.P., Beleza, S., Franceschini, N., Auer, P.L., Robinson, J.G., Kooperberg, C., Peters, U. and Tang, H. (2012) Genome-wide association and population genetic analysis of C-reactive protein in African American and Hispanic American women. Am. J. Hum. Genet., 91, 502-512.
27. Doumatey, A.P., Chen, G., Tekola Ayele, F., Zhou, J., Erdos, M., Shriner, D., Huang, H., Adeleye, J., Balogun, W., Fasanmade, O. et al. (2012) C-reactive protein (CRP) promoter polymorphisms influence circulating CRP levels in a genome-wide association study of African Americans. Hum. Mol. Genet., 21, 3063-3072.
28. Choi, M., Scholl, U.I., Ji, W., Liu, T., Tikhonova, I.R., Zumbo, P., Nayir, A., Bakkaloglu, A., Ozen, S., Sanjad, S. et al. (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. USA, 106, 19096-19101.
29. Ng, S.B., Buckingham, K.J., Lee, C., Bigham, A.W., Tabor, H.K., Dent, K.M., Huff, C.D., Shannon, P.T., Jabs, E.W., Nickerson, D.A. et al. (2010) Exome sequencing identifies the cause of a Mendelian disorder. Nat. Genet., 42, 30-35.
30. Ng, S.B., Turner, E.H., Robertson, P.D., Flygare, S.D., Bigham, A.W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E.E. et al. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature, 461, 272-276.
31. Bilguvar, K., Ozturk, A.K., Louvi, A., Kwan, K.Y., Choi, M., Tatli, B., Yalnizoglu, D., Tuysuz, B., Caglayan, A.O., Gokben, S. et al. (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467, 207-210.
32. Ng, S.B., Bigham, A.W., Buckingham, K.J., Hannibal, M.C., McMillin, M.J., Gildersleeve, H.I., Beck, A.E., Tabor, H.K., Cooper, G.M., Mefford, H.C. et al. (2010) Exomesequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet., 42, 790-793.
33. Sanders, S.J., Murtha, M.T., Gupta, A.R., Murdoch, J.D., Raubeson, M.J., Willsey, A.J., Ercan-Sencicek, A.G., DiLullo, N.M., Parikshak, N.N., Stein, J.L. et al. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 485, 237-241.
34. O'Roak, B.J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J.J., Girirajan, S., Karakoc, E., Mackenzie, A.P., Ng, S.B., Baker, C. et al. (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet., 43, 585-589.
35. Guerreiro, R.J., Lohmann, E., Kinsella, E., Bras, J.M., Luu, N., Gurunlian, N., Dursun, B., Bilgic, B., Santana, I., Hanagasi, H. et al. (2012) Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease. Neurobiol. Aging, 33, 1008.e1017-e1023.
36. Albrechtsen, A., Grarup, N., Li, Y., Sparso, T., Tian, G., Cao, H., Jiang, T., Kim, S.Y., Korneliussen, T., Li, Q. et al. (2013) Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia, 56, 298-310.
37. Lange, L.A., Hu, Y., Zhang, H., Xue, C., Schmidt, E.M., Tang, Z.Z., Bizon, C., Lange, E.M., Smith, J.D., Turner, E.H. et al. (2014) Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am. J. Hum. Genet., 94, 233-245.
38. Peloso, G.M., Auer, P.L., Bis, J.C., Voorman, A., Morrison, A.C., Stitziel, N.O., Brody, J.A., Khetarpal, S.A., Crosby, J.R., Fornage, M. et al. (2014) 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., 94, 223-232.
39. Curocichin, G., Wu, Y., McDade, T.W., Kuzawa, C.W., Borja, J.B., Qin, L., Lange, E.M., Adair, L.S., Lange, L.A. and Mohlke, K.L. (2011) Single-nucleotide polymorphisms at five loci are associated with C-reactive protein levels in a cohort of Filipino young adults. J. Hum. Genet., 56, 823-827.
40. Middelberg, R.P., Ferreira, M.A., Henders, A.K., Heath, A.C., Madden, P.A., Montgomery, G.W., Martin, N.G. and Whitfield, J.B. (2011) Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.BMCMed. Genet., 12, 123.
41. Chasman, D.I., Kozlowski, P., Zee, R.Y., Kwiatkowski, D.J. and Ridker, P.M. (2006) Qualitative and quantitative effects of APOE genetic variation on plasma C-reactive protein, LDL-cholesterol, and apoE protein. Genes Immun., 7, 211-219.
42. Carlson, C.S., Aldred, S.F., Lee, P.K., Tracy, R.P., Schwartz, S.M., Rieder, M., Liu, K., Williams, O.D., Iribarren, C., Lewis, E.C. et al. (2005) Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am. J. Hum. Genet., 77, 64-77.
43. Shrive, A.K., Cheetham, G.M., Holden, D., Myles, D.A., Turnell, W.G., Volanakis, J.E., Pepys, M.B., Bloomer, A.C. and Greenhough, T.J. (1996) Three dimensional structure of human C-reactive protein. Nat. Struct. Biol., 3, 346-354.
44. Adzhubei, I., Jordan, D.M. and Sunyaev, S.R. (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet., doi: 10.1038/nmeth0410-248.
45. Kumar, P., Henikoff, S. and Ng, P.C. (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc., 4, 1073-1081.
46. Judson, R., Brain, C., Dain, B., Windemuth, A., Ruano, G. and Reed, C. (2004) New and confirmatory evidence of an association between APOE genotype and baseline C-reactive protein in dyslipidemic individuals. Atherosclerosis, 177, 345-351.
47. Lee, S., Emond, M.J., Bamshad, M.J., Barnes, K.C., Rieder, M.J., Nickerson, D.A., Christiani, D.C., Wurfel, M.M. and Lin, X. (2012) Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am. J. Hum. Genet., 91, 224-237.
48. Kiezun, A., Garimella, K., Do, R., Stitziel, N.O., Neale, B.M., McLaren, P.J., Gupta, N., Sklar, P., Sullivan, P.F., Moran, J.L. et al. (2012) Exome sequencing and the genetic basis of complex traits. Nat. Genet., 44, 623-630.
49. Kryukov, G.V., Shpunt, A., Stamatoyannopoulos, J.A. and Sunyaev, S.R. (2009) Power of deep, all-exon resequencing for discovery of human trait genes. Proc. Natl. Acad. Sci. USA, 106, 3871-3876.
50. Boncler, M. and Watala, C. (2009) Regulation of cell function by isoforms of C-reactive protein: a comparative analysis. Acta Biochim. Pol., 56, 17-31.
51. Eisenhardt, S.U., Thiele, J.R., Bannasch, H., Stark, G.B. and Peter, K. (2009) C-reactive protein: how conformational changes influence inflammatory properties. Cell Cycle, 8, 3885-3892.
52. Thiele, J.R., Habersberger, J., Braig, D., Schmidt, Y., Goerendt, K., Maurer, V., Bannasch, H., Scheichl, A., Woollard, K.J., von Dobschutz, E. et al. (2014) Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation, 130, 35-50.
53. Davey Smith, G., Lawlor, D.A., Harbord, R., Timpson, N., Rumley, A., Lowe, G.D., Day, I.N. and Ebrahim, S. (2005) Association of C-reactive protein with blood pressure and hypertension: life course confounding and Mendelian randomization tests of causality. Arterioscler. Thromb. Vasc. Biol., 25, 1051-1056.
54. Timpson, N.J., Lawlor, D.A., Harbord, R.M., Gaunt, T.R., Day, I.N., Palmer, L.J., Hattersley, A.T., Ebrahim, S., Lowe, G.D., Rumley, A. et al. (2005) C-reactive protein and its role in metabolic syndrome: Mendelian Randomisation study. Lancet, 366, 1954-1959.
55. Timpson, N.J., Nordestgaard, B.G., Harbord, R.M., Zacho, J., Frayling, T.M., Tybjaerg-Hansen, A. and Smith, G.D. (2011) C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int. J. Obes. (Lond.), 35, 300-308.
56. Yu, C.E., Seltman, H., Peskind, E.R., Galloway, N., Zhou, P.X., Rosenthal, E., Wijsman, E.M., Tsuang, D.W., Devlin, B. and Schellenberg, G.D. (2007) Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association. Genomics, 89, 655-665.
57. Abecasis, G.R., Auton, A., Brooks, L.D., DePristo, M.A., Durbin, R.M., Handsaker, R.E., Kang, H.M., Marth, G.T. and McVean, G.A. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature, 491, 56-65.
58. Bennet, A.M., Di Angelantonio, E., Ye, Z., Wensley, F., Dahlin, A., Ahlbom, A., Keavney, B., Collins, R., Wiman, B., de Faire, U. et al. (2007) Association of apolipoprotein E genotypes with lipid levels and coronary risk. J. Am. Med. Assoc., 298, 1300-1311.
59. Mahley, R.W. and Rall, S.C. Jr. (2000) Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet., 1, 507-537.
60. Rasmussen-Torvik, L.J., Pacheco, J.A., Wilke, R.A., Thompson, W.K., Ritchie, M.D., Kho, A.N., Muthalagu, A., Hayes, M.G., Armstrong, L.L., Scheftner, D.A. et al. (2012) High density GWAS for LDL cholesterol in African Americans using electronic medical records reveals a strong protective variant in APOE. Clin. Transl. Sci., 5, 394-399.
61. Sanna, S., Li, B., Mulas, A., Sidore, C., Kang, H.M., Jackson, A.U., Piras, M.G., Usala, G., Maninchedda, G., Sassu, A. et al. (2011) Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet., 7, e1002198.
62. Curtiss, L.K. (2000) ApoE in atherosclerosis: a protein with multiple hats. Arterioscler. Thromb. Vasc. Biol., 20, 1852-1853.
63. Besnard, S., Silvestre, J.S., Duriez, M., Bakouche, J., Lemaigre-Dubreuil, Y., Mariani, J., Levy, B.I. and Tedgui, A. (2001) Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha. Circ. Res., 89, 1209-1215.
64. Chauvet, C., Vanhoutteghem, A., Duhem, C., Saint-Auret, G., Bois-Joyeux, B., Djian, P., Staels, B. and Danan, J.L. (2011) Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells. PLoS ONE, 6, e22545.
65. Middelberg, R.P., Benyamin, B., de Moor, M.H., Warrington, N.M., Gordon, S., Henders, A.K., Medland, S.E., Nyholt, D.R., de Geus, E.J., Hottenga, J.J. et al. (2012) Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations. Hum. Mol. Genet., 21, 446-455.
66. Chambers, J.C., Zhang, W., Sehmi, J., Li, X., Wass, M.N., Van der Harst, P., Holm, H., Sanna, S., Kavousi, M., Baumeister, S.E. et al. (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet., 43, 1131-1138.
67. Psaty, B.M. and Sitlani, C. (2013) The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. Epidemiology, 24, 346-348.
68. Friedman, G.D., Cutter, G.R., Donahue, R.P., Hughes, G.H., Hulley, S.B., Jacobs, D.R. Jr, Liu, K. and Savage, P.J. (1988) CARDIA: study design, recruitment, and some characteristics of the examined subjects. J. Clin. Epidemiol., 41, 1105-1116.
69. Fried, L.P., Borhani, N.O., Enright, P., Furberg, C.D., Gardin, J.M., Kronmal, R.A., Kuller, L.H., Manolio, T.A., Mittelmark, M.B., Newman, A. et al. (1991) The Cardiovascular Health Study: design and rationale. Ann. Epidemiol., 1, 263-276.
70. Dawber, T.R., Meadors, G.F. and Moore, F.E. Jr. (1951) Epidemiological approaches to heart disease: the Framingham Study. Am. J. Public Health Nations Health, 41, 279-281.
71. Sempos, C.T., Bild, D.E. and Manolio, T.A. (1999) Overview of the Jackson Heart Study: a study of cardiovascular diseases in African American men and women. Am. J. Med. Sci., 317, 142-146.
72. Bild, D.E., Bluemke, D.A., Burke, G.L., Detrano, R., Diez Roux, A.V., Folsom, A.R., Greenland, P., Jacob, D.R. Jr, Kronmal, R., Liu, K. et al. (2002) Multi-ethnic study of atherosclerosis: objectives and design. Am. J. Epidemiol., 156, 871-881.
73. 1998) Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin. Trials, 19, 61-109.
74. Tennessen, J.A., Bigham, A.W., O'Connor, T.D., Fu, W., Kenny, E.E., Gravel, S., McGee, S., Do, R., Liu, X., Jun, G. et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science, 337, 64-69.
75. Li, H. and Durbin, R. (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25, 1754-1760.
76. Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G. and Durbin, R. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics, 25, 2078-2079.
77. McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M. et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res., 20, 1297-1303.
78. Li, H., Ruan, J. and Durbin, R. (2008) Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res., 18, 1851-1858.
79. Bainbridge, M.N., Wang, M., Wu, Y., Newsham, I., Muzny, D.M., Jefferies, J.L., Albert, T.J., Burgess, D.L. and Gibbs, R.A. (2011) Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities. Genome Biol., 12, R68.
80. Challis, D., Yu, J., Evani, U.S., Jackson, A.R., Paithankar, S., Coarfa, C., Milosavljevic, A., Gibbs, R.A. and Yu, F. (2012) An integrative variant analysis suite for whole exome next-generation sequencing data. BMC Bioinformatics, 13, 8.
81. Danecek, P., Auton, A., Abecasis, G., Albers, C.A., Banks, E., DePristo, M.A., Handsaker, R.E., Lunter, G., Marth, G.T., Sherry, S.T. et al. (2011) The variant call format and VCFtools. Bioinformatics, 27, 2156-2158.
82. Sherry, S.T., Ward, M.H., Kholodov, M., Baker, J., Phan, L., Smigielski, E.M. and Sirotkin, K. (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res., 29, 308-311.
83. 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. et al. (2007) PLINK:a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet., 81, 559-575.
84. Wang, K., Li, M. and Hakonarson, H. (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 38, e164.
85. Liu, X., Jian, X. and Boerwinkle, E. (2013) dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum. Mutat., 34, E2393-E2402.
86. R Development Core Team. (2014). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria.
87. Willer, C.J., Li, Y. and Abecasis, G.R. (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics, 26, 2190-2191.