1、Genetics of Complex Traits and DiseasesZHANG Xian-Ning, PhD Tel： ; 88208367 Office: C303, Teaching Building2014/10Any disease is the result of the combined action of genes and environment Classification of genetic disorders:Chromosome disorders:Single-gene disorders:Complex (multifactorial, polygeni

2、c) disorders:Somatic cell genetic disorders:Mitochondrial genetic disorders:ABO blood group 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 chro

3、mosome 1p36, but also on mother and babys being ABO compatible. Hirschsprung disease depends 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, Hir

4、schsprung disease, and adult height.Genetic SusceptibilityAn inherited predisposition to a 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

5、common diseases?Understanding the underlying genetics will lead to understanding the causes, which may lead to better and more specific therapiesIdentification of the responsible genes helps to identify those who are at risk in families and in the population, allowing individualized health assessmen

6、t and targeted preventionHow to Determine the Genetic Components of Complex Diseases?Family, twin and adoption studiesSegregation analysisLinkage analysisAssociation studies and linkage disequilibriumIdentification of DNA sequence variants conferring susceptibilityTrait: Any detectable phenotypic pr

7、operty or character.Qualitative trait: A genetic disease trait that either present 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

8、, blood pressure, serum cholesterol, and body mass index. A quantitative trait shows continued variation under the influence of many different genes. Quantitative trait:Normal distributionHeightWeightShapeColorBlood pressuremetabolic activityreproductive rate Polygenes: small-but-equal effect QTL (q

9、uantitative trait loci)Successive Approximations to a Gaussian Distribution: QTL LiabilityA concept used in disorders which are multifactorially determined to take into account all possible causative factors.thresholdFamilial aggregation: Affected individuals tend to cluster in families. P 149 preva

10、lence of the disease in a relative “r” of an affected personlr= - population prevalence of the disease The higher the familial aggregation, the larger the r. If r = 1, then the relative is at no greater risk than anyone in the general population.Twin studies suffer from many limitationsMonozygotic (

11、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 sibs.Genetic Differences between Identical TwinsAll individuals, even MZs, differ in: th

12、eir 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 partitioning); the pattern of X inactivation, if female. Genetic analysis of quantitative traitsCor

13、relation: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 correlation (r)Positive correlation: r1No correlation: r=0Negative correlation: r cDZ then h2 is

14、high (approaches 1) If cMZ = cDZ then h2 is low (approaches 0) c = concordance Concordance RateTrait or DiseaseMZ twinsDZ twinsHeritabilityAlcoholism0.60.30.6Autism0.920.01Cleft lip/palate0.380.080.6Diabetes, type 10.35-0.50.05-0.10.6-0.8Diabetes, type 20.7-0.90.25-0.40.9-1.0Measles0.950.870.16Schiz

15、ophrenia0.470.120.7Heritability (h2) for Various DiseasesCommon DiseaseMendelian SubtypeInvolved GeneAtherosclerosisFamilial hypercholesterolemiaLDL receptor (LDLR)Breast cancerFamilial breast/ovarian cancerBRCA1, BRCA2Amyotrophic lateralFamilial ALSSuperoxide dismutase (SOD1) SclerosisParkinson dis

16、easeFamilial Parkinson disease-synucleinAlzheimer diseaseFamilial AD PS1, PS2, APPHypertensionLiddle syndromeRenal sodium channel (SCNN1B) Mendelian Forms of Common Complex DiseasesSpectrum of Complexity for Common Diseases: From “Simple” to Complex Alzheimer disease (AD)Complex genetic contribution

17、s to AD may come from:One or more pletely penetrant genes that act independently;Multiple interacting genes; orCombination of genetic and environmental factorsSpectrum of Complexity for Common Diseases: From “Simple” to Complex Alzheimer disease (AD)Familial ADApproximately 10% of patients have a mo

18、nogenic form of AD with highly penetrant, age-related, autosomal dominant inheritancePresents earlier than typical AD: as early as 3rd decade (20s) compared with 7th-9th decades for typical AD Three genes: PS1, PS2, APPEven “Sporadic” AD May Have a Genetic ComponentApolipoprotein E (APOE)Protein com

19、ponent of LDL particleConstituent of amyloid plaques in ADThree alleles: 2, 3, 44/4: 90% show AD by age 802/3: 10% show AD by age 804/- : 25-50% show AD by age 80Environmental factors also involvedAssociation between presence of 4 allele and AD following head trauma is seen in professional boxers Ge

20、netic Testing for APOE GenotypesTesting asymptomatic individuals for 4 remains controversialPoor predictive valueNo effective therapeutic intervention available to prevent onsetAvailable through direct-to-consumer marketingCNVs are common in all genomes surveyed Blue = pathogenic Red = deletion Gree

21、n = duplication Genetic mapping of complex traitsLinkage analysisAssociation studiesGenetic mapping of complex traits 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

22、(1/2) Lod score (z)A measure of the likelihood of genetic linkage between loci.The log (base 10) of the odds that the loci are linked (with bination ) 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

23、.Identity by State (IBS) and Identity by Descent (IBD) Both sib pairs share allele A1. The first sib pair have 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. S

24、ib Pair Analysis By random segregation sib pairs share 0, 1 or 2 parental haplotypes 1/4, 1/2 and 1/4 of 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 a

25、ffected by a recessive condition share both parental haplotypes for the relevant chromosomal segment.Affected sibling-pair analysisSuggested Criteria for Reporting LinkageCategory of linkageExpected No. of occurrences by chances in a whole genome scanRange of approximate p valueRange of approximate

26、lod scoresSuggestive17 x 10-4 3 x 10-52.2 - 3.5Significant0.052 x 10-5 4 x 10-73.6 - 5.3Highly significant0.0015.4Confirmed0.01 in a search of a candidate region that gave significant linkage in a previous independent studyLod score: 3.6 for IBD testing of affected sib pairs, 4.0 for IBSGiven that t

27、he loci are truly linked, with bination fraction q, the likelihood of a meiosis being non binant is 1 - and the likelihood of it being binant is . If the loci are in fact unlinked, the likelihood of a meiosis being either binant or non binant is 1/2. Family AThere are five binants and one non binant

28、.The overall likelihood, given linkage, is (1 - )5. The likelihood given no linkage is (1/2)6The likelihood ratio is (1 - )5. / (1/2)6The lod score, Z, is the logarithm of the likelihood ratio.Family BII1 is phase-unknown.If she inherited A1 with the disease, there are five non binants and one binan

29、t.If she inherited A2 with the disease, there are five binants and one non binant.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 CAt this p

30、oint nonmasochists turn to the computer.Genome-wide scanning: autozygosity mappingPositional cloning Disease mapping - chromosome deletion mutation- linkage analysis Fine mapping Candidate genes- pathogenic mutation screening- functional assayAnother method combines genome scanning and the use of an

31、imal modelsPopulation AssociationsThe low 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

32、between a particular condition and a particular 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 AssociationsAssociation is simply a statistical statement about the co-occurrence of allele

33、s or phenotypes. HLA-DR4, 36% UK / 78%, rheumatoid arthritisA 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 quit

34、e different from linkage, except where the family and the population mergeLinkage 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 populatio

35、n. Linkage creates association within 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. alleli

36、c associationEMLD ( 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 disease. Ot

37、her SNPs are normal variations in the genome.HaplotypeA group of alleles in coupling at closely linked loci, usually inherited as a unit.HaplotypeTag SNPsA select, minimal subset of all the SNPs in a genomic region, chosen because they are in linkage disequilibrium with one another in the population

38、. 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 of LDIf 2 loc

39、i 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 - pApBpossible with the given allele frequencies)2=(

40、pAB - pApB)2/(pApapBpb)Nature, Feb 11,2007A new generation of genomewide association studies (GWAS) has finnaly broken the logjam in cx dis research?Linkage and Association: Complementary TechniquesLinkage operates over a long chromosomal range, scan the entire genome in a few hundred tests250 ASP,

41、300 markers = 1.5-3 x 105 testscandidate regions impracticably large for positional cloningLD short range phenomenonTDT, 300 trios, 25 kb LD = 108 testsNeed to focus on predetermined candidate regions by animal models, known gene, or linkage studiesDifficulties in Identification of DNA Sequence Vari

42、ants Conferring Susceptibility to Cx diseasesNo single gene mutation is necessary or sufficient to cause the diseaseeven a true susceptibility allele will be found in some controls and be absent from some patients.The main determinants of susceptibility may be different in different populationsNo genetic way to identify true determinant among a set of alleles in a strong LDThe genetic variants causing suscepti