医学遗传学课件：Genetics of Complex Traits and Diseases

1、 Any disease is the result of the combined action of genes and environment Classification of genetic disorders: 1. Chromosome disorders: 2. Single-gene disorders: 3. Complex (multifactorial, polygenic) disorders: 4. Somatic cell genetic disorders: 5. Mitochondrial genetic disorders: ABO blood group

2、depends (with rare exceptions) on the genotype at just one locus, the ABO locus at chromosome 9q34. Rhesus hemolytic disease of the newborn depends on the genotypes of mother and baby at the RHD locus at chromosome 1p36, but also on mother and babys being ABO compatible. Hirschsprung disease depends

3、 on the interaction of several genetic loci. Adult stature is determined by the cumulative small effects of many loci. Environmental factors are also important in the etiology of Rhesus hemolytic disease, Hirschsprung disease, and adult height. Genetic Susceptibility An inherited predisposition to a

4、 disease or disorder which is not due to a single-gene cause and is usually the result of a complex interaction of the effects of multiple different genes, i.e. polygenic inheritance. Why study the genetics of common diseases? Understanding the underlying genetics will lead to understanding the caus

5、es, which may lead to better and more specific therapies Identification of the responsible genes helps to identify those who are at risk in families and in the population, allowing individualized health assessment and targeted prevention How to Determine the Genetic Components of Complex Diseases? F

6、amily, twin and adoption studies Segregation analysis Linkage analysis Association studies and linkage disequilibrium Identification of DNA sequence variants conferring susceptibility Trait: Any detectable phenotypic property or character. Qualitative trait: A genetic disease trait that either prese

7、nt or absent. The pattern of inheritance for a qualitative trait is typically monogenetic, which means that the trait is only influenced by a single gene. Quantitative trait: are measurable characteristics such as height, blood pressure, serum cholesterol, and body mass index. A quantitative trait s

8、hows continued variation under the influence of many different genes. Quantitative trait:Normal distribution Height Weight Shape Color Blood pressure metabolic activity reproductive rate Polygenes: small-but-equal effect QTL (quantitative trait loci) Successive Approximations to a Gaussian Distribut

9、ion: QTL Liability A concept used in disorders which are multifactorially determined to take into account all possible causative factors. threshold Familial aggregation: Affected individuals tend to cluster in families. prevalence of the disease in a relative “r” of an affected person l lr= - popula

10、tion prevalence of the disease Twin studies suffer from many limitations Monozygotic (MZ) twins are genetically identical clones and should always be concordant (both the same) for any genetically determined character. Dizygotic (DZ) twins share half their genes on average, the same as any pair of s

11、ibs. Genetic Differences between Identical Twins All individuals, even MZs, differ in: their repertoire of antibodies and T-cell receptors (because of epigenetic rearrangements and somatic cell mutations); somatic mutations in general the numbers of mitochondrial DNA molecules (epigenetic partitioni

12、ng); the pattern of X inactivation, if female. Genetic analysis of quantitative traits Correlation: Heritability: Correlation is a statistical measure of the degree of association of variable phenomena (a measure of the degree of resemblance or relationship between 2 parameters). Coefficient of corr

13、elation (r) Positive correlation: r1 No correlation: r=0 Negative correlation: r1 Cleft lip/palate0.380.080.6 Diabetes, type 10.35-0.50.05-0.10.6-0.8 Diabetes, type 20.7-0.90.25-0.40.9-1.0 Measles0.950.870.16 Schizophrenia0.470.120.7 Heritability (h2) for Various Diseases Common DiseaseMendelian Sub

14、typeInvolved Gene AtherosclerosisFamilial hypercholesterolemiaLDL receptor (LDLR) Breast cancerFamilial breast/ovarian cancerBRCA1, BRCA2 Amyotrophic lateralFamilial ALSSuperoxide dismutase (SOD1) Sclerosis Parkinson diseaseFamilial Parkinson disease -synuclein Alzheimer diseaseFamilial AD PS1, PS2,

15、 APP HypertensionLiddle syndromeRenal sodium channel (SCNN1B) Mendelian Forms of Common Complex Diseases CNVs are common in all genomes surveyed Blue = pathogenic Red = deletion Green = duplication Genetic mapping of complex traits Linkage analysis Association studies Genetic mapping of complex trai

16、ts Linkage analysis: genome scan which analyzes the disease pedigrees using hundreds of polymorphic markers (SNP) throughout the entire genome. L () Lods (log odds score): Z() = log- L (1/2) Lod score (z) A measure of the likelihood of genetic linkage between loci.The log (base 10) of the odds that

17、the loci are linked (with recombination ) rather than unlinked. For mendelian characters a lod score greater than +3 is evidence of linkage;one that is less than 2 is evidence against linkage. Identity by State (IBS) and Identity by Descent (IBD) Both sib pairs share allele A1. The first sib pair ha

18、ve two independent copies of A1 (IBS but not IBD); the second sib pair share copies of the same paternal A1 allele (IBD). The difference is only apparent if the parental genotypes are known. Sib Pair Analysis (A)By random segregation sib pairs share 0, 1 or 2 parental haplotypes 1/4, 1/2 and 1/4 of

19、the time, respectively. (B) Pairs of sibs who are both affected by a dominant condition share one or two parental haplotypes for the relevant chromosomal segment. (C) Pairs of sibs who are both affected by a recessive condition share both parental haplotypes for the relevant chromosomal segment. Aff

20、ected sibling-pair analysis Suggested Criteria for Reporting Linkage Category of linkage Expected No. of occurrences by chances in a whole genome scan Range of approximate p value Range of approximate lod scores Suggestive17 x 10-4 3 x 10-52.2 - 3.5 Significant0.052 x 10-5 4 x 10-73.6 - 5.3 Highly s

21、ignificant 0.0015.4 Confirmed0.01 in a search of a candidate region that gave significant linkage in a previous independent study Lod score: 3.6 for IBD testing of affected sib pairs, 4.0 for IBS Given that the loci are truly linked, with recombination fraction q, the likelihood of a meiosis being n

22、onrecombinant is 1 - and the likelihood of it being recombinant is . If the loci are in fact unlinked, the likelihood of a meiosis being either recombinant or nonrecombinant is 1/2. Family A There are five recombinants and one nonrecombinant. The overall likelihood, given linkage, is (1 - )5. The li

23、kelihood given no linkage is (1/2)6 The likelihood ratio is (1 - )5. / (1/2)6 The lod score, Z, is the logarithm of the likelihood ratio. Family B II1 is phase-unknown. If she inherited A1 with the disease, there are five nonrecombinants and one recombinant. If she inherited A2 with the disease, the

24、re are five recombinants and one nonrecombinant. The overall likelihood is 1/2 (1 - )5. / (1/2)6 + 1/2 (1 - ). 5 / (1/2)6. This allows for either possible phase, with equal prior probability. The lod score, Z, is the logarithm of the likelihood ratio. Family C At this point nonmasochists turn to the

25、 computer. Genome-wide scanning: autozygosity mapping Disease mapping - chromosome deletion mutation - linkage analysis Fine mapping Candidate genes - pathogenic mutation screening - functional assay Another method combines genome scanning and the use of animal models Population Associations The low

26、 success rate of linkage studies for cx traits in the 1990s suggested that many of the susceptibility factors must be relatively weak, highly heterogeneous, or both. Rather than studying affected relatives, association studies seek populationwide associations between a particular condition and a par

27、ticular allele or haplotype somewhere in the genome. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996; 273:1516. Population Associations Association is simply a statistical statement about the co- occurrence of alleles or phenotypes. HLA-DR4, 36% UK / 78%

28、, rheumatoid arthritis A population association can have many possible causes, not all of which are genetic. Direct causation: An epistatic effect: Population stratification: HLA*A1 and Type I error: false positives Linkage disequilibrium (LD): Association is quite different from linkage, except whe

29、re the family and the population merge Linkage is a specific genetic relationship between loci (physical sites on the cs) Association is a relation between specific alleles and/or phenotypes. Linkage does not of itself produce any association in the general population. Linkage creates association wi

30、thin families, but not between unrelated people. Genome-Wide Association Studies (GWAS) Association studies depend on linkage disequilibrium (LD) The occurrence together of 2 or more alleles at closely linked loci more frequently than would be expected by chance. allelic association EMLD (http:/requ

31、/qhuang/ Software/pub.htm) D:0（no LD）1 (complete association) SNP: A change in which a single base in the DNA differs from the usual base at that position. Millions of SNPs have been cataloged in the human genome. Some SNPs such that which causes sickle cell are responsible for dise

32、ase. Other SNPs are normal variations in the genome. Haplotype A group of alleles in coupling at closely linked loci, usually inherited as a unit. Haplotype Tag SNPs A select, minimal subset of all the SNPs in a genomic region, chosen because they are in linkage disequilibrium with one another in th

33、e population. Tag SNPs are useful because they form a minimum set of SNPs whose alleles constitute haplotypes capable of representing all the common haplotypes in that region. HapMap: A set of haplotypes, defined by tag SNPs, distributed throughout the genome, used for association studies. Measures

34、of LD If 2 loci have alleles A, a and B, b with frequencies pA, pa, pB and pb 4 possible haplotype: AB, Ab, aB and ab; pAB, pAb, paB and pab. If no LD, pAB= pApB and so on. The degree of departure, D = pABpab pAbpaB. D=(pAB - pApB )/Dmax (the maximum value of pAB - pApB possible with the given allel

35、e frequencies) 2=(pAB - pApB)2/(pApapBpb) Nature, Feb 11,2007 A new generation of genomewide association studies (GWAS) has finnaly broken the logjam in cx dis research? Linkage and Association: Complementary Techniques Linkage operates over a long chromosomal range, scan the entire genome in a few

36、hundred tests 250 ASP, 300 markers = 1.5-3 x 105 tests candidate regions impracticably large for positional cloning LD short range phenomenon TDT, 300 trios, 25 kb LD = 108 tests Need to focus on predetermined candidate regions by animal models, known gene, or linkage studies Difficulties in Identif

37、ication of DNA Sequence Variants Conferring Susceptibility to Cx diseases No single gene mutation is necessary or sufficient to cause the disease even a true susceptibility allele will be found in some controls and be absent from some patients. The main determinants of susceptibility may be differen

38、t in different populations No genetic way to identify true determinant among a set of alleles in a strong LD The genetic variants causing susceptibility to common diseases may not be obvious mutations May be SNPs in noncoding regions have small effect on promoter activity, RNA splicing or mRNA stability. How