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Haplotype 에 기초한 genetic linkage/ association 의 통계학적 알고리즘 연구

Haplotype 에 기초한 genetic linkage/ association 의 통계학적 알고리즘 연구. 남정모 1) , 김진흠 2) , 강대룡 1) , 신선미 3) , 이윤경 3) , 박정용 3) , 허남욱 3) , 서일 1). 1) 연세대학교 의과대학 예방의학교실 2) 수원대학교 통계정보학과 3) 연세대학교 대학원 보건학과. Background. Linkage Association

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Haplotype 에 기초한 genetic linkage/ association 의 통계학적 알고리즘 연구

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  1. Haplotype에 기초한 genetic linkage/association의 통계학적 알고리즘 연구 남정모1), 김진흠2), 강대룡1), 신선미3), 이윤경3), 박정용3), 허남욱3), 서일1) 1) 연세대학교 의과대학 예방의학교실 2) 수원대학교 통계정보학과 3) 연세대학교 대학원 보건학과

  2. Background LinkageAssociation Recombinant fraction Allelic disequilibrium Family Population - Trio (TDT) - Case-Control - (Affected) Sib-Pair Single locus Tightly linked multi-locus (Haplotype)

  3. Background Why haplotype-based? But … • Haplotype set of closely linked genetic markers present on one chromosome which tends to be inherited together • Many markers are genotyped within a very short physical distance • More informative • Haplotype information is not usually available from genotype information (Haplotype reconstruction) eg. When # of heterozygous loci=c, # of possible haplotype pairs=2c-1

  4. Background (Haplotype ambiguity) • Hypothetical family trio • Probable haplotype pairs • In Sample 1, F’s haplotype uncertainty exists ! • In Sample 2, haplotypes of parents are deducible !

  5. Background Previous researches • Wilson (1997, AHG), Clayton & Jones (1999, AJHG) : Discard families with ambiguous haplotypes • Clayton (1999, AJHG) : likelihood-based but not robust to population admixture • Zhao et al. (2000, AJHG) : How to resolve haplotype ambiguity ? Allocate a conditional probability to each of haplotype group corresponding to a set of genotypes

  6. Haplotype-based TDT (Zhao et al., 2000) • For each g, estimate the number of families : F with {Hi , Hj} transmits Hi and M with {Hk , Hl} transmits Hk • Transmission / Non-transmission table

  7. Haplotype-based TDT (Zhao et al., 2000) • Based on Spielman & Ewens(1996)’s multi-allelic TDT • Remark • Ts&e follows the chi-square distribution with df = h-1 asymptotically ? No except h=2 • Why ? Sham(1997,AJHG) & Lazzeroni and Lange(1998, Hum Hered) + dependency between cell counts • ⇒ obtain empirical p-value by randomization process

  8. Purpose • Propose new haplotype-based linkage / association test • Investigate empirical levels and powers of proposed test statistics by simulation • Test linkage / association between 4 SNPs (A-240T, T-93C, I/D, G2350A ) in ACE (Angiotensin-I Converting Enzyme) gene and hypertension

  9. Proposed haplotype-based Score and LR test • Stuart (1955) • Bradley & Terry (1952)

  10. Simulation studies (A1, A2, D, A3) # of loci = 3 A1 → a1 A2 → a2 A2 → a2 D→ d A3 → a3 A3 → a3 A3 → a3 A3 → a3 H1 H2 H3 H4 H5 H6 H7 H8 Fig.1 Genealogy of four mutations at four loci used in simulation study

  11. Simulation studies • Types of haplotype frequencies • Haplotype with disease susceptible mutant allele = H7 ,H8 • Background risk of disease occurrence = 0.1, 0.2 • RR=1(level); 1.2, 1.6, 2.0, 4.0, 6.0(power) • # of subjects in each population = 200 • Generate genotype data for Case-Control(1 : 2) and Trio • # of replication = 200 ; # of resampling = 100

  12. Configuration of genetic data generating

  13. Empirical levels (5%)

  14. Empirical powers for Conf. I

  15. Empirical powers for Conf. V

  16. Kangwha study • 783 students who were aged of 15 at Kangwha in 1995 were monitored up to 1997 every year • Phenotype : High BP • Case : students experienced at least once SBP>130mmHg or DBP>85mmHg Control : selected from the student having the lowest BP sequentially Case : Control = 101 : 176 • Trio : students whose parents’ genotypes are available among students in Case group, 40 trios • 4 SNPs : A-240T, T-93C, I/D, G2350A of ACE in region 17q23

  17. , Schematic diagram of the human ACE gene illustrating the location of 10 biallelic polymorphisms. Ploymorphisms are numbered in base pairs relative to the start of transcription of the ACE gene. Exons 1-26 are indicated with vertical bars and are numbered intermittently for clarity. Keavney et al., Human Molecular Genetics 1998

  18. Estimated haplotype frequencies † Denote haplotypes corresponding to pair of (I/D, A-240T, T-93C, G2350A) ‡ EH, SAS, Proposed algorithm

  19. P-value of association and linkage test † Normal approximation and Yate’s continuity correction ‡ Zhao et al. (2000, AJHG)’s and Score tests § Zhao, Curtis and Sham (2000, Hum Hered)’s χ2 test

  20. Summary • Investigate single locus-based and haplotype-based association/ linkage test - single locus-based < haplotype-based - population-based <? > family-based • Hypertension is NOT linked with the markers on ACE gene , but… • In the future … - how to reduce the haplotype uncertainty - how to include observations with only one parent or with only sibship - how to combine all types of observations into one test statistic

  21. Thank you

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