GENETIC EPIDEMIOLOGY

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GENETIC EPIDEMIOLOGY

• Institute of Clinical Medicine
• Po-Hsiu Kuo 04/16/2008

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Outline

• Overview of gene mapping
• Allele frequency
• Quantitative genetics
• Genetic component and Heritability
• Hardy-Weinberg Equilibrium
• Linkage Disequilibrium

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Gene mapping
LOCALIZE and then IDENTIFY a locus that regulates
a trait
Association analysis
Linkage analysis
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Allele frequency and genotype frequency

• Allele (gene)
• Genotype frequency? 0.3, 0.6, 0.1
• Allele frequency f(A1) ? 120/200 0.6
• Allele frequency f(A2) ? 80/200 0.4

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Factors influence on allele frequency

• Population size
• Reproduce rate and Survival rate
• Immigration and mutation
• Pattern of assortative mating

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Quantitative genetics

• Study of continuous traits (such as height or
  weight) and its underlying mechanisms
• Combined effect of the many underlying genes
  results in a continuous distribution of
  phenotypic values
• Quantitative genetics is not limited to
  continuous traits, but to all traits that are
  determined by many genes
• Continuous traits are quantitative traits with a
  continuous phenotypic range. They are usually
  polygenic, and may also have a significant
  environmental influence
• Traits with ordinal numbers, such as number of
  bristles on a fruit fly. These traits can be
  either treated as approximately continuous traits
  or as threshold traits
• Some qualitative traits can be treated as if they
  have an underlying quantitative basis, expressed
  as a threshold trait (or multiple thresholds)

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Population level
Genotype frequencies (Random mating)
Allele 1
A (p)
a (q)
A (p)
AA (p2)
Aa (pq)
Allele 2
a (q)
aA (qp)
aa (q2)
Hardy-Weinberg Equilibrium frequencies
P (AA) p2
P (Aa) 2pq
p2 2pq q2 1
P (aa) q2
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Phenotype level
Quantitative traits
e.g. cholesterol levels
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Components of Phenotypic Values

• Phenotype (P) Genotype (G) Environment (E)
• Considering variances (Var), this becomes
• Var(P) Var(G) Var(E) 2 Cov(G,E)
• G A (additive genotypic value) D (dominance
  deviation)
• A breeding value (i.e. the sum of the average
  effects of the two alleles)
• D intra-allelic interaction
• In planned experiments, we can often take
  Cov(G,E) 0
• Heritability

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Heritability

• Proportion of phenotypic variation in a
  population that is attributable to genetic
  variation among individuals
• Variation among individuals may be due to genetic
  and/or environmental factors
• Heritability analyses estimate the relative
  contributions of differences in genetic and
  non-genetic factors to the total phenotypic
  variance in a population.

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Resemblance between relatives
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rMZ rDZ 1
rMZ 1, rDZ 0.5
E
E

rMZ 1, rDZ ?
C
C
e
e
A
A
c
c
a
a
Q
Q
q
q
Twin 1 mole count
Twin 2 mole count
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Twin study

• One of behavioral genetics study design
• Highlighting the role of environmental and
  genetic causes on behavior
• Shared environmental influences common to members
  of family class, parenting styles, education etc
• Shared genes, inherited from parents
• Compares the similarity between twins (MZ vs. DZ)
• Modern history of the twin study derives from Sir
  Francis Galton's pioneering use of twins to study
  the role of genes and environment on human
  development and behavior

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The Law of Hardys

• Assumption
• Radom mating, no selection, no mutation, no
  immigrant
• Question Whats the allele frequency between
  generations?
• Two alleles (A, a)
• F(A) p, f(a) q, pq1
• Frequency of genotype distribution AA, Aa, aa?

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Allele frequency in the next generation

• f(A) p2 ½ (2pq) p(pq) p
• f(a) q2 ½ (2pq) q(pq) q
• Therefore, under previous assumptions, allele
  frequency is unchanged over generations i.e.
  reached equilibrium
• Note a German physician Wilhelm Weinberg made
  the same conclusion as Hardy ? so called
  Hardy-Weinberg Equilibrium (HWE)

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Test for Hardy-Weinberg Equilibrium

• Test for genotype frequency
• Example examining MN blood typing in 6129
  Americans
• Under HWE, test for ?2 S(O-E)2/ E
• First f(M) p 0.539
• f(N) q 0.461

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Test for HWE (conti.)
P0.539, q0.461

• f(MM) p2 0.291, f(MN) 2pq 0.496, f(NN)
  q2 0.212
• ?2 0.00489
• P(?2,df1 ) 0.9
• Conclusion MN blood patterns in this sample are
  in HWE

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Linkage phase

• For two loci, features of being in equilibrium
  means
• p(AB) 2 p(A)p(B)
• Linked two loci, say A1A2/B1B2
• Coupling phase
• Repulsion phase

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Linkage Disequilibrium

• Gametic Association
• At equilibrium, f(AB gamete) PAB PA PB
• Consider 2 alleles are at each of 2 loci with
  random mating, then there are ten possible
  zygotes
• If r is the probability that a gamete is
  recombinant
• In each generation, the amount of gametic
  disequilibrium, measured by PAB - PA PB , is
  reduced by a factor of r
• PAB PAB r D (where D p11 p22 - p12 p21)
• D a quantitative measure of the amount of
  linkage disequilibrium

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Linkage Disequilibrium (conti.)

• Dt(1-r)t D0
• Decay of linkage disequilibrium parameters
  between two loci depends on recombination
  fraction and time (generation)
• Dmax min (p1q2, p2q1), the largest positive
  value
• When p11 p22 0.5 p12 p21 0, max D 0.25
• D D / Dmax, defined by Lewontin (1988)

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Falconer and Mackay (1996)
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Population Admixture

• Admixture

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• D PA1B2 PA2B1-PA1B1 PA2B2
• m p1 q2(1-m) P1 Q2?m q1 p2(1-m) P2
  Q1
• -m p1 p2(1-m) P1 P2?m q1 q 2(1-m) Q1
  Q2
• m (1-m) (p1-P1) (p2-P2)
• Only when p1 P1 or p2 P2 or (p1 P1 and
  p2 P2),
• D 0