A guide to genome-wide association analysis and post-analytic interrogation

Statistics in Medicine

Volumn 34, Issue 28, 2015, Pages 3769-3792

  Reed, Eric ^a   Nunez, Sara ^a   Kulp, David ^b   Qian, Jing ^c   Reilly, Muredach P ^d   Foulkes, Andrea S ^a  

^a MOUNT HOLYOKE COLLEGE   (United States)

^b University of Massachusetts Amherst   (United States)

^c UNIVERSITY OF MASSACHUSETTS   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Ancestry; Bioconductor; Call rate; Genome wide association (GWA) study; Hardy Weinberg equilibrium (HWE); Heatmap; Heterozygosity; IBD; Imputation; Lambda statistic; Manhattan plot; Minor allele frequency (MAF); Parallel processing; Principal component analysis (PCA); Q Q plot; R code; Regional association plot; Relatedness; Sample filtering; SNP filtering; Statistical genomics; Substructure; Tutorial; UCSC Genome Browser

Indexed keywords

ARTICLE; BIOINFORMATICS; COMPUTER PROGRAM; DATA ANALYSIS; GENETIC ASSOCIATION; GENOME ANALYSIS; GENOME WIDE ASSOCIATION ANALYSIS; HUMAN; INFORMATION PROCESSING; POST ANALYTIC INTERROGATION; QUALITY CONTROL; SIGNAL DETECTION; SINGLE NUCLEOTIDE POLYMORPHISM; STATISTICAL ANALYSIS; BIOLOGY; GENETIC DATABASE; GENOME-WIDE ASSOCIATION STUDY; STATISTICS AND NUMERICAL DATA;

COMPUTATIONAL BIOLOGY; DATABASES, GENETIC; GENOME-WIDE ASSOCIATION STUDY; HUMANS; SOFTWARE;

EID: 84961203566     PISSN: 02776715     EISSN: 10970258     Source Type: Journal    
DOI: 10.1002/sim.6605     Document Type: Article

References (56)

1. Laird NM, Lange C. The Fundamentals of Modern Statistical Genetics. Springer-Verlag: New York, 2011.
2. Ziegler A, Konig IR, Pahlke F. A Statistical Approach to Genetic Epidemiology: Concepts and Applications, with an e-Learning Platform (2nd Updated edition). Wiley-Blackwell, 2010.
3. Foulkes AS. Applied Statistical Genetics with r. Springer-Verlag: New York, 2009.
4. Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT. Basic statistical analysis in genetic case-control studies. Nature Protocols. 2011; 6(2): 121-133.
5. Balding DJ. A tutorial on statistical methods for population association studies. Nature Reviews Genetics. 2006; 7(10): 781-791.
6. Laurie CC, Doheny KF, Mirel DB, Pugh EW, Bierut LJ, Bhangale T, Boehm F, Caporaso NE, Cornelis MC, Edenberg HJ, Gabriel SB, Harris EL, Hu FB, Jacobs KB, Kraft P, Landi MT, Lumley T, Manolio TA, McHugh C, Painter I, Paschall J, Rice JP, Rice KM, Zheng X, Weir BS. Quality control and quality assurance in genotypic data for genome-wide association studies. Genetic Epidemiology. 2010; 34(6): 591-602.
7. Gogarten SM, Bhangale T, Conomos MP, Laurie CA, McHugh CP, Painter I, Zheng X, Crosslin DR, Levine D, Lumley T, Nelson SC, Rice K, Shen J, Swarnkar R, Weir BS, Laurie CC. GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies. Bioinformatics. 2012; 28(24): 3329-3331.
8. Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. American Journal of Human Genetics. 2008; 83(3): 311-321.
9. Liu DJ, Peloso GM, Zhan X, Holmen OL, Zawistowski M, Feng S, Nikpay M, Auer PL, Goel A, Zhang H, Peters U, Farrall M, Orho-Melander M, Kooperberg C, McPherson R, Watkins H, Willer CJ, Hveem K, Melander O, Kathiresan S, Abecasis GR. Meta-analysis of gene-level tests for rare variant association. Nature Genetics. 2014; 46(2): 200-204.
10. Hu YJ, Berndt SI, Gustafsson S, Ganna A, Hirschhorn J, North KE, Ingelsson E, Lin D-Y, Genetic Investigation of Anthropometric Traits (GIANT) Consortium . Meta-analysis of gene-level associations for rare variants based on single-variant statistics. American Journal of Human Genetics. 2013; 93(2): 236-248.
11. Chen MH, Yang Q. GWAF: an R package for genome-wide association analyses with family data. Bioinformatics. 2010; 26(4): 580-581.
12. Ott J, Kamatani Y, Lathrop M. Family-based designs for genome-wide association studies. Nature Reviews Genetics. 2011; 12(7): 465-474.
13. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319): 1061-1073.
14. Li MX, Gui HS, Kwan JS, Sham PC. GATES: a rapid and powerful gene-based association test using extended Simes procedure. The American Journal of Human Genetics. 2011; 88(3): 283-293.
15. Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, Hayward NK, Montgomery GW, Visscher PM, Martin NG, Macgregor S, Mann GJ, Kefford RF, Hopper JL, Aitken JF, Giles GG, Armstrong BK. A versatile gene-based test for genome-wide association studies. The American Journal of Human Genetics. 2010; 87(1): 139-145.
16. Huang H, Chanda P, Alonso A, Bader JS, Arking DE. Gene-based tests of association. PLoS Genetics. 2011; 7(7): e1002177.
17. Wang L, Jia P, Wolfinger RD, Chen X, Grayson BL, Aune TM, Zhao Z. An efficient hierarchical generalized linear mixed model for pathway analysis of genome-wide association studies. Bioinformatics. 2011; 27(5): 686-692.
18. Segre AV, Groop L, Mootha VK, Daly MJ, Altshuler D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genetics. 2010; 6(8).
19. Thomas D. Gene-environment-wide association studies: emerging approaches. Nature Reviews Genetics. 2010; 11(4): 259-272.
20. Reilly MP, Li M, He J, Ferguson J, Stylianou I, Mehta N, Burnett M, Devaney J, Knouff C, Thompson J, Horne B, Stewart A, Assimes T, Wild P, Allayee H, Nitschke P, Patel R. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclpmid21378990erosis: two genome-wide association studies. Lancet. 2011; 377(9763): 383-392.
21. Schunkert H, Konig IR, Kathiresan S, Reilly MP, . et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011; 43(4): 333-338.
22. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case-control association studies. Nature Protocols. 2010; 5(9): 1564-1573.
23. Wright S. Coefficients of inbreeding and relationship. American Naturalist. 1922; 56: 330-338.
24. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010; 26(22): 2867-2873.
25. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nature Genetics. 2007; 39(7): 906-913.
26. Edmondson AC, Braund PS, Stylianou IM, Khera AV, Nelson CP, Wolfe ML, Derohannessian SL, Keating BJ, Qu L, He J, Tobin MD, Tomaszewski M, Baumert J, Klopp N, Doring A, Thorand B, Li M, Reilly MP, Koenig W, Samani NJ, Rader DJ. Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol. Circulation: Cardiovascular Genetics. 2011; 4: 145-155.
27. Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, Thompson JR, Ingelsson E, Saleheen D, Erdmann J, Goldstein BA, Stirrups K, Konig IR, Cazier JB, Johansson A, Hall AS, Lee JY, Willer CJ, Chambers JC, Esko T, Folkersen L, Goel A, Grundberg E, Havulinna AS, Ho WK, Hopewell JC, Eriksson N, Kleber ME, Kristiansson K, Lundmark P, Lyytikainen LP, Rafelt S, Shungin D, Strawbridge RJ, Thorleifsson G, Tikkanen E, Van Zuydam N, Voight BF, Waite LL, Zhang W, Ziegler A, Absher D, Altshuler D, Balmforth AJ, Barroso I, Braund PS, Burgdorf C, Claudi-Boehm S, Cox D, Dimitriou M, Do R, Doney AS, El Mokhtari N, Eriksson P, Fischer K, Fontanillas P, Franco-Cereceda A, Gigante B, Groop L, Gustafsson S, Hager J, Hallmans G, Han BG, Hunt SE, Kang HM, Illig T, Kessler T, Knowles JW, Kolovou G, Kuusisto J, Langenberg C, Langford C, Leander K, Lokki ML, Lundmark A, McCarthy MI, Meisinger C, Melander O, Mihailov E, Maouche S, Morris AD, Muller-Nurasyid M, Nikus K, Peden JF, Rayner NW, Rasheed A, Rosinger S, Rubin D, Rumpf MP, Schafer A, Sivananthan M, Song C, Stewart AF, Tan ST, Thorgeirsson G, van der Schoot CE, Wagner PJ, Wells GA, Wild PS, Yang TP, Amouyel P, Arveiler D, Basart H, Boehnke M, Boerwinkle E, Brambilla P, Cambien F, Cupples AL, de Faire U, Dehghan A, Diemert P, Epstein SE, Evans A, Ferrario MM, Ferrieres J, Gauguier D, Go AS, Goodall AH, Gudnason V, Hazen SL, Holm H, Iribarren C, Jang Y, Kahonen M, Kee F, Kim HS, Klopp N, Koenig W, Kratzer W, Kuulasmaa K, Laakso M, Laaksonen R, Lee JY, Lind L, Ouwehand WH, Parish S, Park JE, Pedersen NL, Peters A, Quertermous T, Rader DJ, Salomaa V, Schadt E, Shah SH, Sinisalo J, Stark K, Stefansson K, Tregouet DA, Virtamo J, Wallentin L, Wareham N, Zimmermann ME, Nieminen MS, Hengstenberg C, Sandhu MS, Pastinen T, Syvanen AC, Hovingh GK, Dedoussis G, Franks PW, Lehtimaki T, Metspalu A, Zalloua PA, Siegbahn A, Schreiber S, Ripatti S, Blankenberg SS, Perola M, Clarke R, Boehm BO, O'Donnell C, Reilly MP, Marz W, Collins R, Kathiresan S, Hamsten A, Kooner JS, Thorsteinsdottir U, Danesh J, Palmer CN, Roberts R, Watkins H, Schunkert H, Samani NJ. Large-scale association analysis identifies new risk loci for coronary artery disease. Nature Genetics. 2013; 45(1): 25-33.
28. Li MX, Yeung JM, Cherny SS, Sham PC. Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Human Genetics. 2012; 131(5): 747-756.
29. Li Y, Willer C, Sanna S, Abecasis G. Genotype imputation. Annual Review of Genomics and Human Genetics. 2009; 10: 387-406.
30. Aulchenko YS, Struchalin MV, van Duijn CM. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics. 2010; 11: 134.
31. Browning BL, Browning SR. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. The American Journal of Human Genetics. 2009; 84(2): 210-223.
32. Servin B, Stephens M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genetics. 2007; 3(7): e114.
33. Pei YF, Zhang L, Li J, Deng HW. Analyses and comparison of imputation-based association methods. PLoS One. 2010; 5(5): e10827.
34. Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nature Reviews Genetics. 2010; 11(7): 499-511.
35. Devlin B, Roeder K, Wasserman L. Genomic control, a new approach to genetic-based association studies. Theoretical Population Biology. 2001; 60(3): 155-166.
36. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999; 55(4): 997-1004.
37. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D. Assessing the impact of population stratification on genetic association studies. Nature Genetics. 2004; 36(4): 388-393.
38. Teslovich TM, Musunuru K, Smith AV, Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466: 707-713.
39. Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S., et al. Discovery and refinement of loci associated with lipid levels. Nature Genetics. 2013; 45(11): 1274-1283.
40. Evangelou E, Ioannidis JP. Meta-analysis methods for genome-wide association studies and beyond. Nature Reviews Genetics. 2013; 14(6): 379-389.
41. Wang H, Thomas DC, Pe'er I, Stram DO. Optimal two-stage genotyping designs for genome-wide association scans. Genetic Epidemiology. 2006; 30(4): 356-368.
42. Skol AD, Scott LJ, Abecasis GR, Boehnke M. Optimal designs for two-stage genome-wide association studies. Genetic Epidemiology. 2007; 31(7): 776-788.
43. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, Lin X. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics. 2010; 86(6): 929-942.
44. Qian J, Reed E, Nunez S, Qu L, Reilly MP, Foulkes AS. Testing class-level genetic associations using single-element summary statistics; under review.
45. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics. 2003; 34(3): 267-273.
46. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National academy of Sciences of the United States of America. 2005; 102: 15545-15550.
47. Peng G, Luo L, Siu H, Zhu Y, Hu P, Hong S, Zhao J, Zhou X, Reveille JD, Jin L, Amos CI, Xiong M. Gene and pathway-based second-wave analysis of genome-wide association studies. European Journal of Human Genetics. 2010; 18(1): 111-117.
48. Weng L, Macciardi F, Subramanian A, Guffanti G, Potkin SG, Yu Z, Xie X. SNP-based pathway enrichment analysis for genome-wide association studies. BMC Bioinformatics. 2011; 12: 99.
49. Yu J, Pressoir G, Briggs WH, Vroh Bi I, Yamasaki M, Doebley JF, McMullen MD, Gaut BS, Nielsen DM, Holland JB, Kresovich S, Buckler ES. A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics. 2006; 38(2): 203-208.
50. Lippert C, Listgarten J, Liu Y, Kadie CM, Davidson RI, Heckerman D. FaST linear mixed models for genome-wide association studies. Nature Methods. 2011; 8(10): 833-835.
51. Price AL, Zaitlen NA, Reich D, Patterson N. New approaches to population stratification in genome-wide association studies. Nature Reviews Genetics. 2010; 11(7): 459-463.
52. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E. Variance component model to account for sample structure in genome-wide association studies. Nature Genetics. 2010; 42(4): 348-354.
53. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nature Genetics. 2012; 44(7): 821-824.
54. Zhou X, Stephens M. Efficient multivariate linear mixed model algorithms for genome-wide association studies. Nature Methods. 2014; 11(4): 407-409.
55. Hiersche M, Ruhle F, Stoll M. Postgwas: advanced GWAS interpretation in R. PLoS One. 2013; 8(8): e71775.
56. Bezanson J, Edelman A, Karpinski S, Shah VB. Julia: a fresh approach to numerical computing. arXiv preprint arXiv:1411.1607. 2014.