疾病遗传模型Disease gene models

Disease gene models inlod-score analysisMarcella DevotoThe Children’s Hospital of Philadelphia, University of PennsylvaniaHuman Genetics: Linkage analysis and disease geneticsShort Course, Peking UniversityAugust 10-15, 2015Definition of disease locus model • For monogenic traits, genetic model isdefined by:– mode of inheritance (autosomal or X-linked,dominant or recessive)– penetrance, or probability of being affected givena certain disease locus genotype– disease allele frequencyAutosomal dominant mode of inheritance • Affected individuals usually areheterozygous for disease-causingmutation• Rare homozygotes can be equally or more severely affected• Disease affects both genders equally • Recurrence risk for sibs and children is 50%• May have late onset and/or reduced penetrance• Affected people often able toreproduce even if disease is fatal+/- +/++/+ or +/-+/++/+ +/++/-+/-+/-+/- +/+ or +/-Autosomal dominant mode of inheritancein lod-score analysis• Extended pedigrees, where phase can be determined, are often available• With 100% penetrance, affected and unaffected children of affected individuals are equally informative – Children of unaffected individuals provide no information • With reduced penetrance, information provided by unaffected individuals decreases– Children of unaffected individuals provide some information • Parents-child trios are not informative; at least one more individual (affected or unaffected) must be available• Trios (parents and one affected child) contain no linkage information UNLESS there is association between disease and marker allele (and phases are not equally likely)2 2 1 21 2• Trios (parents and one affected child) contain no linkage information UNLESS there is association between disease and marker allele (and phases are not equally likely)2+/2+ 1-/2+1-/2+NR• Trios (parents and one affected child) contain no linkage information UNLESS there is association between disease and marker allele (and phases are not equally likely)2+/2+ 1-/2+1-/2+NR 2+/2+ 1+/2-1-/2+R• Trios (parents and one affected child) contain no linkage information UNLESS there is association between disease and marker allele (and phases are not equally likely)2+/2+ 1-/2+1-/2+NR 2+/2+ 1+/2-1-/2+RL1 = (1- θ) L2 = θ• Trios (parents and one affected child) contain no linkage information UNLESS there is association between disease and marker allele (and phases are not equally likely)2+/2+ 1-/2+1-/2+NR 2+/2+ 1+/2-1-/2+RL = ½(1- θ) + ½θ = 1/2Autosomal recessive mode of inheritance • Affected individuals are homozygous fordisease-causing mutation; heterozygoteshave normal phenotype• Sometimes have “heterozygote advantage”• Usually observed in small nuclear pedigrees• Both sexes are equally affected• On average, 25% of children of two carriers are affected • Recurrence risk for sibs is 25% • Consanguinity is frequent between parents of patients • Often onset is in pediatric age • A common recessive trait can mimic autosomal dominant inheritance +/- +/- -/- -/- +/+ or +/-Autosomal recessive mode of inheritancein lod-score analysis• Multiple pedigrees are necessary to reach significance; problem with genetic heterogeneity• Usually, phase is unknown; collection of family members (such as grandparents, aunts and uncles, etc) beyond 1st degree relatives of patients is useless unless others are affected• Minimal sampling unit should include two affected children; trios with one affected child are not informative unless parents are consanguineous• Unaffected sibs can be heterozygous (2/3) or homozygous normal (1/3), and they contribute at most 1/5 of the information provided by an affected child• Affected females are heterozygous,affected males hemizygous for disease-causing mutation• In population, frequency of affected females is twice the frequency of affected males• Disease is transmitted by mothers to children of both sex; by fathers, only to daughters• 50% of children of affected mothers, and 100% of daughters of affected fathers, are affected+/-+/-+/-+/+ +/Y+/Y +/Y+/Y +/Y-/Y• Usually only males are affected • Affected females often have cytogenetic anomalies• Disease is transmitted by carrier mothers to 50% of sons • On average, 50% of daughters of carrier mothers are also carriers• 100% of daughters of affected males are carriers+/-+/-+/-+/+ +/Y+/Y -/Y+/Y -/Y-/YX-linked modes of inheritancein lod-score analysis• Large pedigrees may be available• The only informative meioses are those of carrier females since recombination cannot take place in hemizygous males. However, males are useful to determine phase• When penetrance is 100%, affected and unaffected sons (and daughters, if transmission is dominant) of carrier females are equally informative• Information provided by unaffected children decreases as penetrance decreasesMode of inheritance in parameter file2 0 0 5 << NO. OF LOCI, RISK LOCUS, SEXLINKED (IF 1), PROGRAM0 0.0 0.0 0 << MUT LOCUS, MUT MALE, MUT FEM, HAP FREQ (IF 1)1 2 << (order of loci on chromosome)1 2 << AFFECTION, NO. OF ALLELES0.999990 0.00001000 << GENE FREQUENCIES1 << NO. OF LIABILITY CLASSES0 1.0000 1.0000 << PENETRANCES3 2 << ALLELE NUMBERS, NO. OF ALLELES0.50000 0.50000 << GENE FREQUENCIES0 0 << SEX DIFFERENCE, INTERFERENCE (IF 1 OR 2)0.000 << RECOMBINATION VALUES1 0.10000 0.45000 << REC VARIED, INCREMENT, FINISHING VALUEReduced penetrance in linkage analysis • Penetrance is incomplete, or reduced, when notall carriers of the disease genotype are affected • Incomplete penetrance is more often seen in dominant disorders• Penetrance is estimated, usually by segregation analysis, as proportion of affected individuals among carriers of disease genotype• If f<100%, unaffected individuals may be assigned the wrong disease genotype• Affected individuals will still be classified correctly (in the absence of phenocopies)• The actual value of the penetrance only affects the likelihood for unaffected individuals• A possible solution is to perform an “affected-only” analysis• Unaffected individuals do not contribute information about disease gene segregation• It has been shown that lod-score analysis is robust to mispecification of penetrance (assuming the mode of inheritance is correct)• A wrong value of the penetrance should not affect the probability of a type 1 error (false declaration of linkage)• It may however produce a bias in the estimate of the recombination fraction, and cause a reduction in power• If different values of penetrance are tested, a correction for multiple testing is necessaryPhenocopies in linkage analysis• Affected individuals who are not carriers of the disease genotype are called phenocopies• If there are phenocopies, the penetrance of the homozygous normal genotype must be > 0• In this case, the values of penetrance will also affect the likelihood for affected individuals• The values of penetrance for the three disease genotypes must satisfy the condition:Φ = f+/+p2 + f+/-2pq + f-/-q2Disease gene frequency in linkage analysis • Disease allele frequency is usually calculated assuming Hardy-Weinberg equilibrium• If disease locus alleles are:+ = wild type, with frequency p- = mutant, with frequency qthen the three genotypes:+/+ +/- -/-have respective frequencies:p2 2pq q2• Information on disease prevalence, Φ, can be obtained from epidemiological studies • In autosomal dominant disease, affected individuals have genotype +/- or -/-:Φ = 2pq + q2• If disease is rare, q2≈ 0, p ≈ 1:Φ≈ 2qq = Φ/2• In recessive conditions, affected individuals have genotype -/-:Φ = q2q = √Φ• In X-linked conditions, affected males have genotype -/Y:Φ = q• If penetrance, f, is less than 100%, disease prevalence has to be adjusted accordingly • In autosomal dominant disease:Φ≈ 2qf q = Φ/(2f)• In autosomal recessive disease:Φ = q2f q = √(Φ/f)• In X-linked disease:Φ = qf q = Φ/f。