Study Design for Linkage, Association and TDT Studies

1
Study Design for Linkage, Association and TDT
Studies

• ??? Ming-Wei Lin, PhD
• ????????????
• ????????????

2
Collins FS. (1992) Nature genetics 13-6
3
Collins FS. (1992) Nature genetics 13-6
4
Linkage Mapping for Disease Genes

• Linkage analysis
• (Lod score method)
• Allele-sharing methods

5
Gregor Mendel

• The principle of segregation of alleles.
• The principle of independent assortment.

6
Linkage

• Linkage describes the phenomenon whereby allele
  at neighbouring loci are close to one another on
  the same chromosome, they will be transmitted
  together more frequently than chance.

7
Linkage Family
8
Linkage Analysis Family
9
Recombinant Gametes

• Crossing over between two neighbouring loci will
  produce recombinant gametes.

10
Recombination Fraction

• Recombination fraction (?)
• number of recombinant gametes
• ---------------------------------------total
  gametes

11
Estimation of Recombination Fraction

• Direct Method count recombinants.
• Maximum Likelihood Method Unknown
  phases Incomplete penetrance Heterogeneity

12
(No Transcript)
13
(No Transcript)
14
Recombination Fraction

• Recombination fraction is a measure of genetic
  distance.
• 1cM 1 chance of recombination between
  two loci.

15
Likelihood Odds

• Likelihood of data if loci linked at ?
• Likelihood odds Likelihood of
  data if loci unlinked
• L(?lt 0.5)
• L(? 0.5)

16
Lod Score

• L(?lt 0.5)
• Lod score (?) log10 L(? 0.5)

17
Linkage Analysis Methods

• Direct counting recombinants and non-recombinants
• Maximum Likelihood Estimate

18
Phase Known Family
19
Phase Known

• L(?) (?/2)r ((1-?)/2) n-r
• r No. of recombinants
• n All meiosis

20
Lod ScorePhase Known

• L(?) LOD log
• L(? 0.5)
• (?/2) r (1-?) / 2 n-r
• log
• (0.25) n
• log 2n?r(1-?)n-r

21
Phase Unknown Family
22
Phase Unknown

• L(?) 1/2 (?/2)r (1-?)/2n-r 1/2
  (?/2)n-r(1-?)/2r
• r No. of recombinants
• n All meiosis

23
Lod ScorePhase Unknown

• L(?) LOD log
• L(? 0.5)
• 1/2 (?/2) r(1-?)/2 n-r(?/2)n-r (1-?)/2r
  
• log
  
• (0.25) n
• log 2n-1?r(1-?)n-r ?n-r(1-?)r

24
Lod Score - Maximum Likelihood Estimate (Z)

• Can be calculated at any values of ? between 0
  and 0.5, but are conventionally reported at ??
  0, 0.01, 0.05, 0.1, 0.2, 0.3, and 0.4.
• Zmax is the maximum likelihood estimate (MLE) of
  ?.
• Lod score can be converted to a chi-square
  statistic by 2(loge10) ? 4.6.

25
Total Lod Score

• Lod score obtained from individual families can
  be added together to calculate the total lod
  score.

26
Statistical Significance of the Lod Score

• lod score gt 3 evidence of linkage
• 2 lt lod score lt 3 suggestive evidence of linkage
• -2 lt lod score lt 2 uninformative of linkage
• lod score lt -2 exclusion of linkage

27
Is a Pedigree Useful for linkage Analysis?

• Are critical individuals in the pedigrees doubly
  heterozygous at the loci? (Informative)
• Can the offsprings be scored as recombinants or
  nonrecombinants? (Phase)

28
Parameters Assumed in Lod Score Analysis

• Transmission mode of disease
• Recombination fraction
• Trait allele frequencies
• Penetrance values for each possible disease
  phenotypes
• Marker allele frequencies.

29
Advantages of Lod Score Analysis

• Statistically, it is more powerful approach than
  any nonparametric method.
• Utilizes every family member