1. Unit 9: Genetic Epidemiology

2. Unit 9 Learning Objectives: 1. Understand characteristics, uses, strengths, and limitations of genetic epidemiology study designs: ---Family studies ---Twin studies ---Adoption studies ---Migrant studies ---Genetic marker studies 2. Calculate, compare, and interpret concordance rates of disorders between monozygotic and dyzogotic twins. 3.Distinguish between association and linkage genetic marker studies.

3. Unit 9 Learning Objectives: 4. Understand the concept of gene-environment interaction. 5.Understand characteristics and interpret results from gene-environment studies: ---Traditional studies ---Case-only studies ---Case-parental control studies ---Twins studies 6.Distinguish between statistical and biological gene-environment interaction, including assessment of when interaction is present.

4. Background and Definitions

5. Background Definitions: Gene: Particular segment of DNA molecule on a chromosome that determines the nature of an inherited trait. Locus: Site or location on a chromosome occupied by a gene. Allele: One or two or more alternate forms of a gene that occurs at the same locus.

6. Definitions: Genotype: Genetic constitution of an individual, often in reference to a particular trait. Phenotype: Realized expression of the genotype. In epidemiology, genotype is modified by the environment to affect the phenotype. Proband: The individual in a family that brings attention to the investigator (e.g. the case or control proband of a set of twins). Background

7. Case-control design (covered in-depth in Unit 10) is particularly well-suited to current genetic epidemiology studies because: 1) Genetic markers are stable – no reliance on individual recall. 2) Temporal relationship to environmental factorsis known. 3)Good for studying rare disorders. Background

8. As stated in Unit 1, Introduction, ALL chronic diseases have “multi-factorial” etiololgies: Minimally, the individual must be genetically susceptible to the disorder: AND There must be at least some interaction with the environment. Background

9. Classic Example of Gene-Environment Interaction: ---Persons with HLA-B27 are approximately 90 times more likely to develop ankylosing spondylitis than persons without HLA-B27 BUT ---Only 10% of all persons with HLA-B27 will develop ankylosing spondylitis. Background

10. Gene-Environment Disease Heterogeneity ---Keep in mind that for many chronic diseases, there may be “hereditary” (familial) and “non- hereditary” (sporadic) forms of the disease Example: BRCA1 and inherited breast cancer. ---In many instances, the inherited form, which still requires environmental interaction, often occurs at an earlier age of onset, and may have an overall poorer prognosis. Background

11. Study Designs in Genetic Epidemiology

12. Study Designs in Genetic Epidemiology 1)Family Studies 2)Twin Studies 3) Adoption Studies 4) Migrant Studies 5) Genetic Marker Studies ---Gene/Environment interactions Overall, basic strategy of these designs are to: a)Hold environment constant:  allow genetic factors to vary b)Hold genetics constant:  allow environmental factors to vary Traditional Recent

13. Study Designs in Genetic Epidemiology 1)Family Studies 2)Twin Studies 3) Adoption Studies 4) Migrant Studies 5) Genetic Marker Studies ---Gene/Environment interactions Traditional Recent In general, the “traditional” studies have been used to assess the relative contribution of genetics to disease occurrence, whereas the “recent” studies also attempt to identify factors (e.g. genes) that play a causal role in disease development.

14. Family Studies Family Studies: vary genetics, keep environment constant: 1)Identify individual with particular disorder (case-proband) – determine rates of the disorder in relatives of the proband. 2)Identify individual without the disorder of interest (control-proband) – determine rates of the disorder in relatives of the proband. 3)Calculate prevalence ratio between relatives of case and relatives of control proband.

15. Family Studies Proband Relatives CaseControl Prevalence ratio (PR) = (3 / 5) / (1 / 5) = 3.0 NOTE: Unlike incidence, the upper limit of the PR is markedly restricted if the disorder of interest is common in the general population.

16. Family Studies Limitations of Family Studies: a) Important environmental factors (e.g. SES, social support, etc.) also tend to be “familial.” b)There may be “assortative mating” – the tendency for those with particular disorders to mate preferentially with those who have similar disorders – may lead to overestimate of genetic effect.

17. Family Studies Other Uses of Family Studies: a)Identify probable mode of transmission of disorders (e.g. dominant or recessive, autosomal or X-linked, etc.). b)Examine validity of diagnostic categories by assessing specificity of transmission of symptom patterns and disorders. c)Investigate phenotypic and etiologic heterogeneity. d)Assess co-morbidity of disorders within families.

18. Twin Studies Twin Studies: vary genetics, keep environment constant: 1)Identify one twin with disorder of interest. 2)Assess whether other twin has the disorder of interest. 3)Calculate the concordance rate (CR) 4)Compare concordance rates between monozygotic (MZ) and dyzogotic (DZ) twins. 5)To support genetic etiology, concordance rates for MZ twins should exceed rate for DZ twins.

19. Concordance rate: (pairwise method): # twin pairs concordant CR PW = ------------------------------------------ total # twin pairs Concordance rate: (probandwise method): 2C 1 + C 2 CR PB = --------------------------------------------------------- 2C 1 + C 2 + D Where C 1 = Concordant pairs: both twins independently ascertained C 2 = Concordant pairs: only one twin independently ascert. D = Number of discordant pairs Twin Studies

20. Pairwise concordance is used when the probability of selecting both case probands as twins is very low (e.g. selecting one proband case from each city). Probandwise concordance is used when the probability of selecting both case probands as twins is not rare (e.g. selecting every third person as a proband case from a local registry of disease cases). The probandwise method usually results in somewhat higher concordance rates. Twin Studies

21. +- +AB -CD Twin 1 Twin 2 MZ TwinsDZ Twins +- +AB -CD Twin 1 Twin 2 CR MZ = A / (A + B + C)CR DZ = A / (A + B + C) Genetic contribution: CR MZ / CR DZ Note: Discordance rate = (B + C) / (A + B + C)

22. The null value for the concordance ratio between MZ and DZ (e.g. no genetic contribution) is 1.0. However, if the value exceeds 1.0, there still remains the possibility that MZ twins share more similar environments than DZ twins. This also includes a more similar intrauterine environment. Also, may be publication bias against studies with low concordance rates in MZ twins. Note: Can also compare concordance of continuous variables by correlation coefficient. Twin Studies

23. +- +3048 -621256 Twin 1 Twin 2 MZ TwinsDZ Twins +- +32130 -1262210 Twin 1 Twin 2 In the above example, is there evidence supporting a genetic contribution to development of the disorder? Does the disorder appear to have a strong environmental component?

24. Twin Studies +- +3048 -621256 Twin 1 Twin 2 MZ TwinsDZ Twins +- +32130 -1262210 Twin 1 Twin 2 CR MZ = A / (A + B + C)CR DZ = A / (A + B + C) Genetic contribution: CR MZ / CR DZ CR MZ = (30 / 140) = 0.2143CR DZ = (32 / 288) = 0.1111 CR MZ / CR DZ = 0.2143 / 0.1111 = 1.93

25. Twin Studies +- +3048 -621256 Twin 1 Twin 2 MZ TwinsDZ Twins +- +32130 -1262210 Twin 1 Twin 2 CR MZ / CR DZ = 0.2143 / 0.1111 = 1.93 The MZ/DZ ratio of 1.93 suggests that genetics have a strong influence on development of the disorder. The relatively low concordance rates among both MZ & DZ twins also suggest a strong environmental component.

26. Some Other Uses of Twin Studies: a)MZ twins reared apart give unique (but rare) opportunity to study influence of genetics in the absence of shared environmental factors. b)Can look at children of discordant MZ twins. If the rate of the disorder in the children of the twins is similar, suggests genetic susceptibility that may be prevented (not expressed) in the presence of environmental factors. Twin Studies

27. Twin Studies – Discordant MZ twins MZ Twins Children Twin 1Twin 2 Genetic susceptibility not expressed in some instances. Children

28. Important Features of Twin Studies: a)Twins constitute about 1.8% of adult population. Use of twin registries allows study in the community rather than the hospital (avoids treatment seeking bias and lack of generalizability). b)When 2 or more disorders are studied in twins, can estimate comorbidity due to shared genetic and shared environmental factors. c)Keep in mind that the “equal environment” assumption between MZ and DZ twins may be suspect. Twin Studies

29. Adoption Studies: vary environment, keep genetics constant: 1)Based on premise that if genes are important, familial transmission should occur in the biologic,but not adoptive family. If environment is important, familial transmission should occur in the adoptive rather than biologic family. 2)Three major adoption study designs: --Parent-as-proband design --Adoptee-as-proband design --Cross-fostering design (most powerful) Adoption Studies

30. Adoption Studies: a)Parent-as-proband design: Compares rate of illness in the adopted offspring of parents with and without the disorder of interest. If genetic factors are important, rates of illness should be higher in adopted children of ill parents compared with adopted children of well parents. Adoption Studies

31. Adoption Studies – Parent-as-Proband Biological Parents Adopted Offspring Parent 1Parent 2 Suggests genetic heritability Adopted Offspring

32. b)Adoptee-as-proband design: Start with ill and well adoptees, and examine rates of illness in both biologic and adoptive relatives. If biologic relatives show higher rates of illness than adoptive relatives, suggests a genetic component. However, if adoptive relatives show higher rates of illness, environmental hypothesis gains support. Adoption Studies

33. Adoption Studies – Adoptee-as-Proband Biologic Relatives Adoptee 1 Adoptee 2 Adoptive Relatives Biologic Relatives Adoptive Relatives (Suggests genetic component)

34. Cross-fostering design: Compares rates of illness for 2 groups of adoptees: Group 1: Adoptee has well biologic parents, raised by ill adoptive parents. Group 2: Adoptee has ill biologic parents, raised by well adoptive parents. Higher rates of illness in Group 1 suggests non-genetic mode of transmission. Adoption Studies

35. Adoption Studies – Cross Fostering Design Biologic (Suggests environmental component) Parent of Adoptees Adoptive Adoptees BiologicAdoptive Adoptees

36. Limitations of Adoption Studies: a)Limited generalizability since adoptees and their families not representative of the general population. b)Adoptees are often at greater risk of illness than non-adopted children (e.g psychiatric disorders). c)Parents of adopted children are known to have higher rates of some disorders (e.g. psychopathology). d)May be difficult to find sample of adoptees separated from parents at birth (e.g. biologic relationship “contaminated” by environment of biologic parents). Adoption Studies