医学遗传与胚胎发育 Chapter 10 Polygenic or Multifactorial inheritance disorders

1、Polygenic or Multifactorialinheritance disorders1OverviewDefinition: Polygenic or multifactorial inheritance disorders result from a combination of multiple genetic and environmental factors.Complex disorders: Disorders that are proven heritable, yet show no clear mode as medelian diseases.More than

2、 one gene - polygenicInteraction between genes - epistasisInteraction between genes and environment - multifactorial 2Examples of polygenic ormultifactorial inheritance disorders Congenital malformations:congenital heart defectsneural tube defectscleft lip/palatepyloric stenosis(幽门狭窄）congenital hip

3、dysplasia（先天性髋关节发育不良）Common non-communicable diseases:asthmaschizophrenia（精神分裂症）diabetes mellitus（糖尿病）hypertension3456Examples of polygenic ormultifactorial inheritance traitsHeightWeightEye color Skin colorIQ Blood pressure7questionAre Mendels laws not applicable for the genes involved in polygenic

4、 or multifactorial inheritance disorders ?8Features of polygenesCo-dominant (等显性) - No one gene is dominant or recessive to another. - for each locus, the alleles are transmitted according to Mendels laws Minor gene (微效基因)Additive effect (累加效应) - each gene adds or detracts a small amount from the ph

5、enotypeMajor gene (主基因效应)9To be affected or not depends on a balancebetween the number and function of good andbad genes and environmental factors10 family studies twin concordance studies dizygous (DZ) vs monozygous (MZ) twins common environment: twins raised in different environment concordant: bo

6、th affected or neither affected genetically determined: 100% MZ twins should be concordant, 50% DZ twins should be concordantenvironmental: MZ=DZ adoption studies, population and immigration studiesEvidence for multifactorial inheritence increased incidence of a disease in particular families common

7、 environment: check not related individuals (spouses)11Determining the incidence of a disease in twins helps define whether genetic and enviromentalDiseaseConcordanceIdentical(MZ)Non-identical(DZ)Diabetes mellitus56%11%Coronary artery disease19%9%Asthma47%24%Rheumatoid arthritis34%7%Cleft lip and pa

8、late38%8%Manic depressive psychosis67%5%12Distribution of diseases in populationQualitative traitssingle gene traits Disease state is QualitativeAffected vs. unaffectedShow trait vs. do not show traitHbS or normal?Quantitative traitspolygenic or multifactorial traits Height ? quantify in inchesWeigh

9、t ? quantify in pounds 13Qualitative traitsSingle-gene inheritance: Mendelian inheritanceIncidence of 1ST degree relatives: AR 25% or AD 50%14Quantitative traitsPolygenic inheritance: Not Mendelian inheritanceIncidence of 1ST degree relatives: 1%10%15Polygenes and phenotypic distributionAssume 3 pai

10、rs of non-linked blood pressure related genes, each with a frequency of 0.5:Locus A: A1, A2; Locus B: B1, B2 Locus C: C1, C2*2gene increases blood pressure; *1gene decreases blood pressure.A total of 8 kinds of gametes and 27 kinds of zygotes can be formed.161718 combinations of the genes (blood pre

11、ssure)19Environment and phenotypic distributionAssume 3 pairs of environmental factors, each with a frequency of 0.5:Factor of nutrition: N+, N-Factor of stress: S+, S-Factor of emotion: E+, E-(+) indicates conditions beneficial to blood pressure(-) indicates conditions disadvantageous to blood pres

12、sure20Combinations of the environmental factors21GE+Quantitative traits produce a continuum of phenotypes shown as a symmetrical bell-shaped curve22The normal (Gaussian) distribution23The liability /threshold model of MF diseases24Liability（易患性）According to the liability/threshold model, all of the

13、factors which influence the development of a multifactorial disorder, whether genetic or environmental, can be considered as a single entity known as liability. i.e. Liability represents the probability of an individual to develop a disease or defect , which is the sum of the genetic and environment

14、al influences. Threshold: The liabilities of all individuals in a population form a continuous variable, a threshold exists above which the abnormal phenotype is expressed. Individuals on the right side of the threshold line represent those affected by the disorder.25Liability curve of general popul

15、ation vs that of the relatives of the affectedThe curve for relatives of affected is shifted to the right; so the familial incidence is higher than the general population incidence.26Susceptibility（易感性） An individuals genetic background (genotype of the multi-loci) plays important roles in determini

16、ng the probability of developing a disease or defect. The influence of genes on the probability of an individual to develop a disease is defined as susceptibility. It could be considered as genetic liability.everyone has a certain susceptibility to a disease.The susceptibility is low or high and fol

17、lows a Gaussian distribution in the population.Under a given circumstance，threshold is determined by the effect of minimum number of genes on the defect. 27notesLiability and susceptibility are applicable to an individual or a population.They are quantitative or numerical value.VL=VG+VEVS=VG 28Quest

18、ionAre the genes and the environmental factors equally important to any MF disease?How to determine the relative contributions of genes and environment to a MF disease?29Heritability( H or h2,遗传度)Heritability is defined as the proportion of the total phenotypic variance of a quantitative trait that

19、is caused by genes.Heritability is a measure of the extent to which different alleles at various loci are responsible for the variability in quantitative trait among a population. 30heritability01The higher the heritability, the greater is the contribution of genetic differences among people in caus

20、ing variability of the trait.31HeritabilityHeritability (H) = proportion of the trait that is controlled by geneticsH= 100 % trait is fully geneticH = 0 % trait is fully environmentalmultifactorial traits are somewhere in between32Estimating heritabilityFalconer formula (1965): h2=b/k b=(Xg-Xr)/agHo

21、lzinger formula (1929):MZ: Monozygotic twin DZ: Dizygotic twin333435Example using Falconer formula Ventricular septal defect(室间隔缺损)qg= 0.1%, qr= 3.3%, k = 1/2b = (XgXr)/ag = (3.090 1.838) / 3.367 = 0.37h2= b/k = 0.37 / 0.5 = 0.74 = 74%36Exampleusing Holzinger formulaManic-depressive psychosis (躁狂抑郁性

22、精神病） ：CMZ=67% CDZ=5% = (0.67 0.05) / (1 0.05) = 0.6526 = 65.26%37Heritability of some MFD 38Significance of heritabilityHeritability is a measure of the contribution of genetic differences among a population in causing variability of the trait. Heritability is a statistic concept for population, whi

23、ch is not applicable to individuals.Heritability of a trait based on a specific population in specific environments is not applicable to other populations and environments. -Heritability can not be in isolation from the population group and environments in which the estimate is made.39Characteristic

24、s of inheritance of MFDDiseases show familial aggregation but do not conform to any simple mendelian pattern of inheritance. They are determined by the additive effects of many genes at different loci together with the effect of environmental factors.The traits show a continuous distribution in gene

25、ral population, which closely resembles a normal distribution. 40Characteristics of inheritance of MFDThe disease is more common among the close relatives of the proband than in the less closely related. - Recurrence risks for relatives decline as the degree of relatedness decreases.Note: Recurrence

26、 risks represents average risk and will vary among different families.Recurrence risk estimation4142Characteristics of inheritance of MFDRecurrence risk increases with the number of affected relatives. Recurrence risk estimation43Characteristics of inheritance of MFD Recurrence risk increases with t

27、he severity of the defect.Recurrence risk estimation44Characteristics of inheritance of MFD If two sexes have a different probability of being affected, the less likely sex, if affected, is more likely to produce an affected offspring. Proband Children(%)sonsdaughtersfather5.52.4mother19.47.3Populat

28、ion incidence0.50.1Recurrence risk estimation45Characteristics of inheritance of MFDEdwards Formula When h2=70%-80%, qg=0.1-1% qr= qgeg: The incidence of cleft lip+palate in population in China is 0.17%, the heritability of the disease is 76%, then we can estimate the incidence of the first degree r

29、elatives as:qr = qg = 0.0017 4%Recurrence risk estimation46Characteristics of inheritance of MFDGreater concordance for disease is expected among monozygotic versus dizygotic twins.Consanguinity increases recurrence risk. 47Question?Which following factors increase recurrence risks in a particular f

30、amily? A. Close relationship to proband B. High heritability of disorder C. Proband of more rarely affected sex D. Severe or early onset disease E. Multiple family members affected48Genetic Counsel on MFDWhat happens when parents ask you the risk of having a child with a complex disorder?Can not cal

31、culate an exact statistical likelihood based on Mendels lawsInstead give:Heritability estimatesEmpiric Risk49Study methods of MFDcandidate gene analysiswhole genome scansQuantitative Trait Loci (QTL) analysis i.e. regions associated with phenotypeAnimal Models combined approachStrategies for disease

32、 gene identification50Methods for disease gene identificationlinkage analysis To search for the co-transmission of a marker locus(genetic marker) in families with the disease.association studies An higher frequency of particular alleles in affected than unaffected individuals in the population sugge

33、sts that the product of that allele plays a role in the pathogenesis of the disease.51Linkage analysismodel-based (parametric) linkage applicable for single gene traitsmodel-free (non-parametric) linkage Model-free methods solely depend on the assumption that two affected relatives will have disease

34、-predisposing alleles in common. 52Association studiesCase-Control Studies Genome-wide association studies, GWAS The most common approach of GWAS compares two large groups of individuals, one healthy control group and one case group affected by a disease. All individuals in each group are genotyped

35、for the majority of common known SNPs. The exact number of SNPs are typically one million or more.For each of these SNPs, it is then investigated if theallele frequencyis significantly different between the case and the control group.5354NHGRI GWA Catalog/GWAStudieswww.ebi.ac.uk/fgpt/gwas/ Published

36、 Genome-Wide Associations through 12/2012Published GWA at p5X10-8 for 17 trait categories55Association studieslinkage disequilibriumInpopulation genetics,linkage disequilibriumis the non-random association ofallelesat differentloci. i.e. the presence of statistical associations between alleles at different loci that are different from what would be expected if alleles were independently, randomly sampled based on their individual allele