Endocrinol Metab.  2011 Sep;26(3):187-192. 10.3803/EnM.2011.26.3.187.

Phenotype-Genotype Association Study: From GWAS to NGS

• Ahn SM

• KMID: 2169167
• DOI: http://doi.org/10.3803/EnM.2011.26.3.187

Abstract

No abstract available.

Figure

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  Fig. 1 The effects of recombination. The copy of a chromosome in generation III is a mosaic of parts of all four grandparental copies of that chromosome. Since recombination does not occur at a single nucleotide resolution, a block of DNA (or a haplotype block) is inherited together.

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  Fig. 2 The logic behind gene hunting. Since genome is inherited in haplotype blocks, all parts in the same block are essentially associated. A. A marker is physically associated with a gene (they are inherited as a block). If we find a marker that can segregate diseased and normal population, this marker can be further used for finding disease-associated genes. B. Positional cloning. Using additional markers providing "linkage coverage" of a portion of the chromosome, we can narrow down the area to identify candidate genes.

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  Fig. 3 Sanger sequencing and next-generation sequencing. In the conventional Sanger sequencing using chain-termination method, only one clone can sequenced per reaction (A). In NGS, millions of clones can be sequenced in parallel, which decreases the sequencing cost dramatically (B).

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  Fig. 4 Sequencing cost per megabase of DNA sequence.

Reference

1. Rosenberg CE. Disease in history: frames and framers. Milbank Q. 1989. 67:Suppl 1. 1–15.

2. Behçet H. Uber rezidivierende Aphthose durch ein Virus verursachte Geschwure am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr. 1937. 105:1152–1157.

3. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med. 1995. 332:1280–1284.

4. Huntington JL, Dueck A. Handling missing data. Curr Probl Cancer. 2005. 29:317–325.

5. Nussbaum RL, McInnes RR, Willard HF. Genetics in Medicine. 2008. 7th ed. Korea: Epublic;485.

6. Feero WG, Guttmacher AE, Collins FS. Genomic medicine--an updated primer. N Engl J Med. 2010. 362:2001–2011.

7. Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, Cole FS, Curnutte JT, Orkin SH. Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location. Nature. 1986. 322:32–38.

8. Anderson D. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study. Am J Dis Child. 1938. 56:344–399.

9. Hartwell L, Hood L, Goldberg ML, Silver LM, Reynolds A. Genetics: from genes to genomes. 2000. 2nd ed. McGraw-Hill College;387–398.

10. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983. 306:234–238.

11. Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000. 405:847–856.

12. Hindorff LA, Junkins HA, Hall PN, Mehta JP, Manolio TA. A catalog of published genome-wide association studies. Cited on Sept. 4th, 2011. Available at: www.genome.gov/gwastudies.

13. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001. 409:860–921.

14. Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays. Nat Genet. 1999. 21:20–24.

15. Al-Chalabi A. Al-Chalabi A, Almasy L, editors. Ch. 8. Genome-wide association studies. Genetics of complex human diseases: a laboratory manual. 2009. New York: Cold Spring Harbor Laboratory Press.

16. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009. 461:747–753.

17. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segre AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Bostrom K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jorgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proenca C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparso T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010. 42:579–589.

18. Yamauchi T, Hara K, Maeda S, Yasuda K, Takahashi A, Horikoshi M, Nakamura M, Fujita H, Grarup N, Cauchi S, Ng DP, Ma RC, Tsunoda T, Kubo M, Watada H, Maegawa H, Okada-Iwabu M, Iwabu M, Shojima N, Shin HD, Andersen G, Witte DR, Jorgensen T, Lauritzen T, Sandbaek A, Hansen T, Ohshige T, Omori S, Saito I, Kaku K, Hirose H, So WY, Beury D, Chan JC, Park KS, Tai ES, Ito C, Tanaka Y, Kashiwagi A, Kawamori R, Kasuga M, Froguel P, Pedersen O, Kamatani N, Nakamura Y, Kadowaki T. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet. 2010. 42:864–868.

19. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990. 250:1684–1689.

20. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010. 141:210–217.

21. Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008. 40:695–701.

22. "Frederick Sanger - Autobiography". Nobelprize.org. 2011. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1980/sanger.html.

23. Hartwell L, Hood L, Goldberg ML, Silver LM, Reynolds A. Genetics: from genes to genomes. 2000. 2nd ed. Boston: McGraw-Hill College;302–307.

24. Venter C. SY Noh . A life decoded. 2009. Seoul: Chusubat.

25. Brenner S, Johnson M, Bridgham J, Golda G, Lloyd DH, Johnson D, Luo S, McCurdy S, Foy M, Ewan M, Roth R, George D, Eletr S, Albrecht G, Vermaas E, Williams SR, Moon K, Burcham T, Pallas M, DuBridge RB, Kirchner J, Fearon K, Mao J, Corcoran K. Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol. 2000. 18:630–634.

26. Hall SS. Revolution postponed. Sci Am. 2010. 303:60–67.

27. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010. 11:415–425.

28. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010. 8:e1000294.

29. Johansen CT, Wang J, Lanktree MB, Cao H, McIntyre AD, Ban MR, Martins RA, Kennedy BA, Hassell RG, Visser ME, Schwartz SM, Voight BF, Elosua R, Salomaa V, O'Donnell CJ, Dallinga-Thie GM, Anand SS, Yusuf S, Huff MW, Kathiresan S, Hegele RA. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010. 42:684–687.

30. Edwards TL, Song Z, Li C. Enriching targeted sequencing experiments for rare disease alleles. Bioinformatics. 2011. 27:2112–2118.