Genetics of Complex Traits and Diseases

1. Genetics of Complex Traits and Diseases 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A705, Research Building 2012/09

2. Genetic Susceptibility易感性 • An 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.

3. Any disease is the result of the combined action of genes and environment Classification of genetic disorders: • Chromosome disorders: • Single-gene disorders: • Complex (multifactorial, polygenic) disorders: • Somatic cell genetic disorders: • Mitochondrial genetic disorders:

4. 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 chromosome 1p36, but also on mother and baby's 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, Hirschsprung disease, and adult height.

5. Why study the genetics of common diseases? • Understanding the underlying genetics will lead to understanding the causes, 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

6. How to Determine the Genetic Components of Complex Diseases? • Family, twin and adoption studies • Segregation analysis • Linkage analysis • Association studies and linkage disequilibrium • Identification of DNA sequence variants conferring susceptibility

7. Trait:Any detectable phenotypic property 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, blood pressure, serum cholesterol, and body mass index. A quantitative trait shows continued variation under the influence of many different genes.

8. Quantitative trait:Normal distribution • Height • Weight • Shape • Color • Blood pressure • metabolic activity • reproductive rate Polygenes: small-but-equal effect QTL (quantitative trait loci)

9. Successive Approximations to a Gaussian Distribution: QTL

11. Liability易患性 • A concept used in disorders which are multifactorially determined to take into account all possible causative factors.

13. Familial aggregation: Affected individuals tend to cluster in families. prevalence of the disease in a relative “r” of an affected person lr= --------------------------------------------------- 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.

14. 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) twinsshare half their genes on average, the same as any pair of sibs.

16. Genetic Differences between Identical Twins • All individuals, even monozygotic twins, 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 partitioning); • the pattern of X inactivation, if female.

17. Genetic analysis of quantitative traits • Correlation: • Heritability:

18. 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).

19. Coefficient of correlation (r) • Positive correlation: r>1 • No correlation: r=0 • Negative correlation: r<1

20. Heritability (h2)遗传率: The proportion of the total variation of a character attributable to genetic as opposed to environment factors. CMZ -- CDZ h2= ----------------------- 100 -- CDZ • If cMZ >> cDZthen h2 is high (approaches 1) • If cMZ = cDZ then h2 is low (approaches 0) [c = concordance]

21. Heritability (h2) for Various Diseases Concordance Rate Trait or DiseaseMZ twinsDZ twinsHeritability Alcoholism 0.6 0.3 0.6 Autism 0.92 0.0 >1 Cleft lip/palate 0.38 0.08 0.6 Diabetes, type 1 0.35-0.5 0.05-0.1 0.6-0.8 Diabetes, type 2 0.7-0.9 0.25-0.4 0.9-1.0 Measles 0.95 0.87 0.16 Schizophrenia 0.47 0.12 0.7

22. Mendelian Forms of Common Complex Diseases Common DiseaseMendelian SubtypeInvolved Gene AtherosclerosisFamilial hypercholesterolemiaLDL receptor (LDLR) Breast cancerFamilial breast/ovarian cancerBRCA1, BRCA2 Amyotrophic lateralFamilial ALSSuperoxide dismutase (SOD1) Sclerosis Parkinson disease Familial Parkinson disease-synuclein Alzheimer disease Familial ADPS1, PS2, APP HypertensionLiddle syndromeRenal sodium channel (SCNN1B)

23. Spectrum of Complexity for Common Diseases: From “Simple” to Complex Alzheimer disease (AD) Complex genetic contributions to AD may come from: One or more incompletely penetrant genes that act independently; Multiple interacting genes; or Combination of genetic and environmental factors

24. Spectrum of Complexity for Common Diseases: From “Simple” to Complex Alzheimer disease (AD) Familial AD Approximately 10% of patients have a monogenic form of AD with highly penetrant, age-related, autosomal dominant inheritance Presents earlier than typical AD: as early as 3rd decade (20s) compared with 7th-9th decades for typical AD Three genes: PS1, PS2, APP

25. Even “Sporadic” AD May Have a Genetic Component Apolipoprotein E (APOE) Protein component of LDL particle Constituent of amyloid plaques in AD Three alleles: 2, 3, 4 4/4: >90% show AD by age 80 2/3: <10% show AD by age 80 4/- : 25-50% show AD by age 80 Environmental factors also involved Association between presence of 4 allele and AD following head trauma is seen in professional boxers

26. Genetic Testing for APOE Genotypes Testing asymptomatic individuals for 4 remains controversial Poor predictive value No effective therapeutic intervention available to prevent onset Available through direct-to-consumer marketing

29. CNVs are common in all genomes surveyed … • Blue = pathogenic • Red = deletion • Green = duplication

30. And sequence variants are even more common…

31. Sequence Variants of Uncertain Clinical Significance:Lessons from BRCA1/BRCA2 Complete sequencing of both genes in over 150,000 people >10,000 deleterious mutations and variants identified Each week, 10-20 new ones detected B. Ward (Myriad Genetics), personal communication with Prof. Grody WW,UCLA

32. Genetic mapping of complex traits • Linkage analysis • Association studies

33. Genetic mapping of complex traits Linkage analysis:genome scan which analyzes the disease pedigrees using hundreds of polymorphic markers (STR) throughout the entire genome. L (θ) • Lods (log odds score): Z(θ) = log[------------ ] L (1/2)

34. 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 recombination θ) 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.

35. 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.

36. Sib 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 affected by a recessive condition share both parental haplotypes for the relevant chromosomal segment.

37. Affected sibling-pair analysis

38. Suggested Criteria for Reporting Linkage Lod score: 3.6 for IBD testing of affected sib pairs, 4.0 for IBS

40. Given that the loci are truly linked, with recombination fraction q, the likelihood of a meiosis being nonrecombinant is 1 - θ and the likelihood of it being recombinant is θ. • If the loci are in fact unlinked, the likelihood of a meiosis being either recombinant or nonrecombinant is 1/2. • Family AThere are five recombinants and one nonrecombinant. • The overall likelihood, given linkage, is (1 - θ)5. θ • The likelihood given no linkage is (1/2)6 • The likelihood ratio is (1 - θ)5. θ / (1/2)6 • The 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 nonrecombinants and one recombinant. • If she inherited A2 with the disease, there are five recombinants and one nonrecombinant. • The overall likelihood is 1/2 [(1 - θ)5. θ / (1/2)6] + 1/2 [(1 - θ). θ 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 point nonmasochists turn to the computer.

41. Genome-wide scanning: autozygosity mapping

42. Positional cloning • Disease mapping - chromosome deletion mutation - linkage analysis • Fine mapping • Candidate genes - pathogenic mutation screening - functional assay

43. Another method combines genome scanning and the use of animal models

44. Population Associations • The 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 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.

45. Population Associations • Association is simply a statistical statement about the co-occurrence of alleles or phenotypes. HLA-DR4, 36% UK / 78%, 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):

46. Association is quite different from linkage, except where 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 within families, but not between unrelated people.

47. Genome-Wide Association Studies (GWAS)

48. 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://request.mdacc.tmc.edu/qhuang/ Software/pub.htm) • D’:0（no LD）~±1 (complete association)

49. SNP: A change in which a single base in the DNA differs from the usual base at that position. Millions of SNP's have been cataloged in the human genome. Some SNPs such that which causes sickle cell are responsible for disease. Other SNPs are normal variations in the genome.