The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes

Human Molecular Genetics

Volumn 21, Issue 9, 2012, Pages 2111-2123

  Cusanovich, Darren A ^a   Billstrand, Christine ^a   Zhou, Xiang ^a   Chavarria, Claudia ^a   De Leon, Sherryl ^a   Michelini, Katelyn ^a   Pai, Athma A ^a   Ober, Carole ^a   Gilad, Yoav ^a  

^a UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; T LYMPHOCYTE RECEPTOR;

ADULT; ARTICLE; ASTHMA; CLINICAL ARTICLE; FEMALE; GENE EXPRESSION; GENE LOCUS; GENE REPLICATION; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENOME ANALYSIS; HUMAN; LYMPHOCYTE COUNT; MALE; PRIORITY JOURNAL;

ASTHMA; CELL LINE; DATA INTERPRETATION, STATISTICAL; ETHNIC GROUPS; GENE EXPRESSION PROFILING; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LYMPHOCYTE COUNT; QUANTITATIVE TRAIT LOCI;

EID: 84859260926     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/dds021     Document Type: Article

References (83)

1. Manolio, T.A., Collins, F.S., Cox, N.J., Goldstein, D.B., Hindorff, L.A., Hunter, D.J., McCarthy, M.I., Ramos, E.M., Cardon, L.R., Chakravarti, A. et al. (2009) Finding the missing heritability of complex diseases. Nature, 461, 747-753, doi:10.1038/nature08494.
2. So, H., Gui, A.H.S., Cherny, S.S. and Sham, P.C. (2011) Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet. Epidemiol., 35, 310-317. doi:10.1002/gepi.20579.
3. Clarke, A.J. and Cooper, D.N. (2010) GWAS: heritability missing in action? Eur. J. Hum. Genet., 18, 859-861. doi:10.1038/ejhg.2010.35.
4. Eichler, E.E., Flint, J., Gibson, G., Kong, A., Leal, S.M., Moore, J.H. and Nadeau, J.H. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet., 11, 446-450. doi:10.1038/nrg2809.
5. Gibson, G. (2010) Hints of hidden heritability in GWAS. Nat. Genet., 42, 558-560. doi:10.1038/ng0710-558.
6. Lee, S.H., Wray, N.R., Goddard, M.E. and Visscher, P.M. (2011) Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet., 88, 294-305. doi:16/j.ajhg.2011.02.002.
7. Maher, B. (2008) Personal genomes: the case of the missing heritability. Nature, 456, 18-21. doi:10.1038/456018a.
8. Makowsky, R., Pajewski, N.M., Klimentidis, Y.C., Vazquez, A.I., Duarte, C.W., Allison, D.B. and de los Campos, G. (2011) Beyond missing heritability: prediction of complex traits. PLoS Genet., 7, e1002051. doi:10.1371/journal.pgen.1002051.
9. Kutalik, Z., Whittaker, J., Waterworth, D., Beckmann, J.S. and Bergmann, S. (2011) Novel method to estimate the phenotypic variation explained by genome-wide association studies reveals large fraction of the missing heritability. Genet. Epidemiol., 35, 341-349. doi:10.1002/gepi.20582.
10. Yang, J., Benyamin, B., McEvoy, B.P., Gordon, S., Henders, A.K., Nyholt, D.R., Madden, P.A., Heath, A.C., Martin, N.G., Montgomery, G.W. et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nat. Genet., 42, 565-569. doi:10.1038/ng.608.
11. Speliotes, E.K., Willer, C.J., Berndt, S.I., Monda, K.L., Thorleifsson, G., Jackson, A.U., Allen, H.L., Lindgren, C.M., Luan, J., Magi, R. et al. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet., 42, 937-948. doi:10.1038/ng.686.
12. Moffatt, M.F., Kabesch, M., Liang, L., Dixon, A.L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A., Rietschel, E. et al. (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature, 448, 470-473. doi:10.1038/nature06014.
13. Halapi, E., Gudbjartsson, D.F., Jonsdottir, G.M., Bjornsdottir, U.S., Thorleifsson, G., Helgadottir, H., Williams, C., Koppelman, G.H., Heinzmann, A., Boezen, H.M. et al. (2010) A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur. J. Hum. Genet., 18, 902-908. doi:10.1038/ejhg.2010.38.
14. Lluis, A., Schedel, M., Liu, J., Illi, S., Depner, M., von Mutius, E., Kabesch, M. and Schaub, B. (2011) Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion. J. Allergy Clin. Immunol., 127, 1587-1594.e6. doi:10.1016/j.jaci.2011.03.015.
15. Verlaan, D.J., Berlivet, S., Hunninghake, G.M., Madore, A.-M., Larivière, M., Moussette, S., Grundberg, E., Kwan, T., Ouimet, M., Ge, B. et al. (2009) Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am. J. Hum. Genet., 85, 377-393. doi:16/j.ajhg.2009.08.007.
16. Verlaan, D.J., Ge, B., Grundberg, E., Hoberman, R., Lam, K.C.L., Koka, V., Dias, J., Gurd, S., Martin, N.W., Mallmin, H. et al. (2009) Targeted screening of cis-regulatory variation in human haplotypes. Genome Res., 19, 118-127. doi:10.1101/gr.084798.108.
17. Nicolae, D.L., Gamazon, E., Zhang, W., Duan, S., Dolan, M.E. and Cox, N.J. (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet., 6, e1000888. doi:10.1371/journal.pgen.1000888.
18. Nica, A.C., Montgomery, S.B., Dimas, A.S., Stranger, B.E., Beazley, C., Barroso, I. and Dermitzakis, E.T. (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet., 6, e1000895. doi:10.1371/journal.pgen.1000895.
19. Ding, J., Gudjonsson, J.E., Liang, L., Stuart, P.E., Li, Y., Chen, W., Weichenthal, M., Ellinghaus, E., Franke, A., Cookson, W. et al. (2010) Gene expression in skin and lymphoblastoid cells: refined statistical method reveals extensive overlap in cis-eQTL signals. Am. J. Hum. Genet., 87, 779-789. doi:10.1016/j.ajhg.2010.10.024.
20. Murphy, A., Chu, J.-H., Xu, M., Carey, V.J., Lazarus, R., Liu, A., Szefler, S.J., Strunk, R., Demuth, K., Castro, M. et al. (2010) Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. Hum. Mol. Genet, 19, 4745-4757. doi:10.1093/hmg/ddq392.
21. Zeller, T., Wild, P., Szymczak, S., Rotival, M., Schillert, A., Castagne, R., Maouche, S., Germain, M., Lackner, K., Rossmann, H. et al. (2010) Genetics and beyond-the transcriptome of human monocytes and disease susceptibility. PLoS ONE, 5, e10693, doi:10.1371/journal.pone.0010693.
22. Naukkarinen, J., Surakka, I., Pietiläinen, K.H., Rissanen, A., Salomaa, V., Ripatti, S., Yki-Järvinen, H., van Duijn, C.M., Wichmann, H.-E., Kaprio, J. et al. (2010) Use of genome-wide expression data to mine the 'Gray Zone' of GWA studies leads to novel candidate obesity genes. PLoS Genet., 6, e1000976. doi:10.1371/journal.pgen.1000976.
23. Zhong, H., Beaulaurier, J., Lum, P.Y., Molony, C., Yang, X., MacNeil, D.J., Weingarth, D.T., Zhang, B., Greenawalt, D., Dobrin, R. et al. (2010) Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet., 6, e1000932. doi:10.1371/journal.pgen.1000932.
24. Ober, C., Abney, M. and McPeek, M.S. (2001) The genetic dissection of complex traits in a founder population. Am. J. Hum. Genet., 69, 1068-1079. doi:10.1086/324025.
25. Ober, C., Pan, L., Phillips, N., Parry, R. and Kurina, L.M. (2006) Sex-specific genetic architecture of asthma-associated quantitative trait loci in a founder population. Curr. Allergy Asthma Rep., 6, 241-246. doi:10.1007/s11882-006-0041-4.
26. Chong, J.X., Oktay, A.A., Dai, Z., Swoboda, K.J., Prior, T.W. and Ober, C. (2011) A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites. Eur. J. Hum. Genet., 19, 1045-1051. doi:10.1038/ejhg.2011.85.
27. Bellenguez, C., Ober, C. and Bourgain, C. (2009) Linkage analysis with dense SNP maps in isolated populations. Hum. Hered., 68, 87-97, doi:10.1159/000212501.
28. Jones, R.G., Plas, D.R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M.J. and Thompson, C.B. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 18, 283-293, doi:16/j.molcel.2005.03.027.
29. Tamás, P., Hawley, S.A., Clarke, R.G., Mustard, K.J., Green, K., Hardie, D.G. and Cantrell, D.A. (2006) Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med., 203, 1665-1670. doi:10.1084/jem.20052469.
30. Steiner, J., Marquardt, N., Pauls, I., Schiltz, K., Rahmoune, H., Bahn, S., Bogerts, B., Schmidt, R.E. and Jacobs, R. (2011) Human CD8(+) T cells and NK cells express and secrete S100B upon stimulation. Brain Behav. Immun., 25, 1233-1241. doi:10.1016/j.bbi.2011.03.015.
31. Moffatt, M.F., Gut, I.G., Demenais, F., Strachan, D.P., Bouzigon, E., Heath, S., von Mutius, E., Farrall, M., Lathrop, M. and Cookson, W.O.C.M. (2010) A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med., 363, 1211-1221. doi:10.1056/NEJMoa0906312.
32. Torgerson, D.G., Ampleford, E.J., Chiu, G.Y., Gauderman, W.J., Gignoux, C.R., Graves, P.E., Himes, B.E., Levin, A.M., Mathias, R.A., Hancock, D.B. et al. (2011) Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet., 43, 887-892, doi:10.1038/ng.888.
33. Ober, C. and Hoffjan, S. (2006) Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun., 7, 95-100. doi:10.1038/sj.gene.6364284.
34. Rogers, A.J., Raby, B.A., Lasky-Su, J.A., Murphy, A., Lazarus, R., Klanderman, B.J., Sylvia, J.S., Ziniti, J.P., Lange, C., Celedon, J.C. et al. (2009) Assessing the reproducibility of asthma candidate gene associations, using genome-wide data. Am. J. Respir. Crit. Care Med., 179, 1084-1090. doi:10.1164/rccm.200812-1860OC.
35. Nicolae, D.L. and Ober, C. (2009) (Too) great expectations: the challenges in replicating asthma disease genes. Am. J. Respir. Crit. Care Med., 179, 1078-1079. doi:10.1164/rccm.200903-0456ED.
36. Vercelli, D. (2008) Discovering susceptibility genes for asthma and allergy. Nat. Rev. Immunol., 8, 169-182. doi:10.1038/nri2257.
37. Nalls, M.A., Couper, D.J., Tanaka, T., van Rooij, F.J.A., Chen, M.-H., Smith, A.V., Toniolo, D., Zakai, N.A., Yang, Q., Greinacher, A. et al. (2011) Multiple loci are associated with white blood cell phenotypes. PLoS Genet., 7, e1002113. doi:10.1371/journal.pgen.1002113.
38. Okada, Y., Hirota, T., Kamatani, Y., Takahashi, A., Ohmiya, H., Kumasaka, N., Higasa, K., Yamaguchi-Kabata, Y., Hosono, N., Nalls, M.A. et al. (2011) Identification of nine novel loci associated with white blood cell subtypes in a Japanese population. PLoS Genet., 7, e1002067. doi:10.1371/journal.pgen.1002067.
39. Reiner, A.P., Lettre, G., Nalls, M.A., Ganesh, S.K., Mathias, R., Austin, M.A., Dean, E., Arepalli, S., Britton, A., Chen, Z. et al. (2011) Genome-wide association study of white blood cell count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT). PLoS Genet., 7, e1002108. doi:10.1371/journal.pgen.1002108.
40. Cheung, V.G., Spielman, R.S., Ewens, K.G., Weber, T.M., Morley, M. and Burdick, J.T. (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature, 437, 1365-1369. doi:10.1038/nature04244.
41. Stranger, B.E., Nica, A.C., Forrest, M.S., Dimas, A., Bird, C.P., Beazley, C., Ingle, C.E., Dunning, M., Flicek, P., Koller, D. et al. (2007) Population genomics of human gene expression. Nat. Genet., 39, 1217-1224. doi:10.1038/ng2142.
42. Veyrieras, J.-B., Kudaravalli, S., Kim, S.Y., Dermitzakis, E.T., Gilad, Y., Stephens, M. and Pritchard, J.K. (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet., 4, e1000214. doi:10.1371/journal.pgen.1000214.
43. Dimas, A.S., Deutsch, S., Stranger, B.E., Montgomery, S.B., Borel, C., Attar-Cohen, H., Ingle, C., Beazley, C., Gutierrez Arcelus, M., Sekowska, M. et al. (2009) Common regulatory variation impacts gene expression in a cell type-dependent manner. Science, 325, 1246-1250. doi:10.1126/science.1174148.
44. Bullaughey, K., Chavarria, C.I., Coop, G. and Gilad, Y. (2009) Expression quantitative trait loci detected in cell lines are often present in primary tissues. Hum. Mol. Genet., 18, 4296-4303. doi:10.1093/hmg/ddp382.
45. Choy, E., Yelensky, R., Bonakdar, S., Plenge, R.M., Saxena, R., De Jager, P.L., Shaw, S.Y., Wolfish, C.S., Slavik, J.M., Cotsapas, C. et al. (2008) Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet., 4, e1000287. doi:10.1371/journal.pgen.1000287.
46. Stark, A.L., Zhang, W., Mi, S., Duan, S., O'Donnell, P.H., Huang, R.S. and Dolan, M.E. (2010) Heritable and non-genetic factors as variables of pharmacologic phenotypes in lymphoblastoid cell lines. Pharmacogenomics J., 10, 505-512. doi:10.1038/tpj.2010.3.
47. Çalişkan, M., Cusanovich, D.A., Ober, C. and Gilad, Y. (2011) The effects of EBV transformation on gene expression levels and methylation profiles. Hum. Mol. Genet., 20, 1643-1652. doi:10.1093/hmg/ddr041.
48. Redon, R., Ishikawa, S., Fitch, K.R., Feuk, L., Perry, G.H., Andrews, T.D., Fiegler, H., Shapero, M.H., Carson, A.R., Chen, W. et al. (2006) Global variation in copy number in the human genome. Nature, 444, 444-454. doi:10.1038/nature05329.
49. Stranger, B.E., Forrest, M.S., Dunning, M., Ingle, C.E., Beazley, C., Thorne, N., Redon, R., Bird, C.P., de Grassi, A., Lee, C. et al. (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science, 315, 848-853. doi:10.1126/science.1136678.
50. Yu, W., Clyne, M., Khoury, M.J. and Gwinn, M. (2010) Phenopedia and Genopedia: disease-centered and gene-centered views of the evolving knowledge of human genetic associations. Bioinformatics, 26, 145-146. doi:10.1093/bioinformatics/btp618.
51. Liu, P., Li, P. and Burke, S. (2010) Critical roles of Bcl11b in T-cell development and maintenance of T-cell identity. Immunol. Rev., 238, 138-149. doi:10.1111/j.1600-065X.2010.00953.x.
52. Gutierrez, A., Kentsis, A., Sanda, T., Holmfeldt, L., Chen, S.-C., Zhang, J., Protopopov, A., Chin, L., Dahlberg, S.E., Neuberg, D.S. et al. (2011) The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood, 118, 4169-4173. doi:10.1182/blood-2010-11-318873.
53. Vanvalkenburgh, J., Albu, D.I., Bapanpally, C., Casanova, S., Califano, D., Jones, D.M., Ignatowicz, L., Kawamoto, S., Fagarasan, S., Jenkins, N.A. et al. (2011) Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J. Exp. Med., 208, 2069-2081. doi:10.1084/jem.20102683.
54. Ku, M., Koche, R.P., Rheinbay, E., Mendenhall, E.M., Endoh, M., Mikkelsen, T.S., Presser, A., Nusbaum, C., Xie, X., Chi, A.S. et al. (2008) Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet., 4, e1000242. doi:10.1371/journal.pgen.1000242.
55. Mochizuki-Kashio, M., Mishima, Y., Miyagi, S., Negishi, M., Saraya, A., Konuma, T., Shinga, J., Koseki, H. and Iwama, A. (2011) Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood, 118, 6553-6561. doi:10.1182/blood-2011-03-340554.
56. Squazzo, S.L., O'Geen, H., Komashko, V.M., Krig, S.R., Jin, V.X., Jang, S.-W., Margueron, R., Reinberg, D., Green, R. and Farnham, P.J. (2006) Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res., 16, 890-900. doi:10.1101/gr.5306606.
57. Jameson, S.C. (2002) Maintaining the norm: T-cell homeostasis. Nat. Rev. Immunol., 2, 547-556. doi:10.1038/nri853.
58. Michalek, R.D., Gerriets, V.A., Jacobs, S.R., Macintyre, A.N., MacIver, N.J., Mason, E.F., Sullivan, S.A., Nichols, A.G. and Rathmell, J.C. (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol., 186, 3299-3303. doi:10.4049/jimmunol.1003613.
59. Michalek, R.D. and Rathmell, J.C. (2010) The metabolic life and times of a T-cell. Immunol. Rev., 236, 190-202. doi:10.1111/j.1600-065X.2010.00911.x.
60. Jutel, M. and Akdis, C.A. (2011) T-cell subset regulation in atopy. Curr. Allergy Asthma Rep., 11, 139-145. doi:10.1007/s11882-011-0178-7.
61. Robinson, D.S. (2010) The role of the T cell in asthma. J. Allergy Clin. Immunol., 126, 1081-1091. doi:16/j.jaci.2010.06.025.
62. Umetsu, D.T. and Dekruyff, R.H. (2006) Immune dysregulation in asthma. Curr. Opin. Immunol., 18, 727-732. doi:10.1016/j.coi.2006.09.007.
63. Ober, C., Tsalenko, A., Parry, R. and Cox, N.J. (2000) A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am. J. Hum. Genet., 67, 1154-1162. doi:10.1016/S0002-9297(07)62946-2.
64. Weiss, L.A., Pan, L., Abney, M. and Ober, C. (2006) The sex-specific genetic architecture of quantitative traits in humans. Nat. Genet., 38, 218-222. doi:10.1038/ng1726.
65. Ober, C., Tan, Z., Sun, Y., Possick, J.D., Pan, L., Nicolae, R., Radford, S., Parry, R.R., Heinzmann, A., Deichmann, K.A. et al. (2008) Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N. Engl. J. Med., 358, 1682-1691. doi:10.1056/NEJMoa0708801.
66. Ober, C., Nord, A.S., Thompson, E.E., Pan, L., Tan, Z., Cusanovich, D., Sun, Y., Nicolae, R., Edelstein, C., Schneider, D.H. et al. (2009) Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J. Lipid Res., 50, 798-806. doi:10.1194/jlr.M800515-JLR200.
67. Karolchik, D. (2004) The UCSC Table Browser data retrieval tool. Nucleic Acids Res., 32, 493D-496D. doi:10.1093/nar/gkh103.
68. Goecks, J., Nekrutenko, A. and Taylor, J. (2010) Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome Biol., 11, R86. doi:10.1186/gb-2010-11-8-r86.
69. Blankenberg, D., Von Kuster, G., Coraor, N., Ananda, G., Lazarus, R., Mangan, M., Nekrutenko, A. and Taylor, J. (2010) Galaxy: a web-based genome analysis tool for experimentalists. Curr. Protoc. Mol. Biol., Chapter 19, 19.10.1-19.10.21. doi:10.1002/0471142727.mb1910s89.
70. Korn, J.M., Kuruvilla, F.G., McCarroll, S.A., Wysoker, A., Nemesh, J., Cawley, S., Hubbell, E., Veitch, J., Collins, P.J., Darvishi, K. et al. (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet., 40, 1253-1260. doi:10.1038/ng.237.
71. Gentleman, R.C., Carey, V.J., Bates, D.M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J. et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol., 5, R80. doi:10.1186/gb-2004-5-10-r80.
72. Du, P., Kibbe, W.A. and Lin, S.M. (2008) Lumi: a pipeline for processing Illumina microarray. Bioinformatics, 24, 1547-1548. doi:10.1093/bioinformatics/btn224.
73. Abney, M., Ober, C. and McPeek, M.S. (2002) Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: Fasting serum-insulin level in the Hutterites. Am. J. Hum. Genet., 70, 920-934. doi:10.1086/339705.
74. Abney, M., McPeek, M.S. and Ober, C. (2000) Estimation of variance components of quantitative traits in inbred populations. Am. J. Hum. Genet., 66, 629-650. doi:10.1086/302759.
75. Pruim, R.J., Welch, R.P., Sanna, S., Teslovich, T.M., Chines, P.S., Gliedt, T.P., Boehnke, M., Abecasis, G.R. and Willer, C.J. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics, 26, 2336-2337. doi:10.1093/bioinformatics/btq419.
76. Storey, J.D. and Tibshirani, R. (2003) Statistical significance for genomewide studies. PNAS, 100, 9440-9445, doi:10.1073/pnas.1530509100.
77. Backes, C., Keller, A., Kuentzer, J., Kneissl, B., Comtesse, N., Elnakady, Y.A., Muller, R., Meese, E. and Lenhof, H.-P. (2007) GeneTrail-advanced gene set enrichment analysis. Nucleic Acids Res., 35, W186-W192. doi:10.1093/nar/gkm323.
78. Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T. et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet., 25, 25-29. doi:10.1038/75556.
79. Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M. and Hirakawa, M. (2010) KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res., 38, D355-D360. doi:10.1093/nar/gkp896.
80. Kanehisa, M. and Goto, S. (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res., 28, 27-30. doi:10.1093/nar/28.1.27.
81. Benjamini, Y. and Hochberg, Y. (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Statist. Soc. B, 57, 289-300. http://www.jstor.org/stable/2346101.
82. Kang, H.M., Ye, C. and Eskin, E. (2008) Accurate discovery of expression quantitative trait loci under confounding from spurious and genuine regulatory hotspots. Genetics, 180, 1909-1925. doi:10.1534/genetics.108.094201.
83. Johnson, A.D., Handsaker, R.E., Pulit, S.L., Nizzari, M.M., O'Donnell, C.J. and de Bakker, P.I.W. (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics, 24, 2938-2939. doi:10.1093/bioinformatics/btn564.