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Principles of Genetic Epidemiology

Kirsten Ohm Kyvik. Principles of Genetic Epidemiology. Genetic epidemiology.

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Principles of Genetic Epidemiology

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  1. Kirsten Ohm Kyvik Principles of GeneticEpidemiology

  2. Geneticepidemiology • Geneticepidemiology deals with the etiology, distribution, and control of disease (epidemiology) in groups of relatives and with inheritedcauses of disease (genetics) in populations (adapted from Morton and Chung 1978)

  3. Steps in genetic epidemiology • Evidence for familialaggregation • Is familialaggregation due to genes or environment? • Specificgeneticmechanisms • Takingadvantageof designs involving • Families • Twins • Adoptees and their families

  4. Fundamentals • Definition of phenotype • Classification of phenotype • Natural history of phenotype

  5. Adaptation of concept of causation • Family status changes risk profile • Observations on family members not independent • Boundary between cohort and case-control studies is blurred

  6. Multifactorial inheritance Monogenic Quantitativ Mød en forsker

  7. T R E S H O L D M O D E L

  8. Family studies

  9. Design of familiestudies • Identify probands – ”ascertainmentprobability” • Information on phenotype in relatives (1.degree, 2. degree etc.) • Comparegroups of relatives • Compare with background population

  10. Familialaggregation = geneticaetiology? • Against: • Effect of:

  11. Groups of relatives • Risk of siblingscompared to risk in parent-offspring • RR(sib) = RR(par) • RR(sib) >> RR(par • RR(sib) and RR(par) small, but biggerthan population risk

  12. Expected risk pattern

  13. Parkinson’sdisease in Iceland(Sveinbjørnsdottir et al. NEJM, 2000)

  14. Genetic epidemiology of infantile hypertrophic pyloric stenosis • The IHPS register • Funenbased • Cases from 1950 to 2004 • A total of 892 cases, 870 identified in CPR • Questionnaire send to all cases • Reply from 65%

  15. Smoothed prevalence

  16. Recurrence risk in relatives

  17. Twin studies

  18. Aims • What is the risk/recurrencerisk in twins • Is a phenotypegenetically determined • Aetiological models • Size of genetic variation / heritability • Genes, markers, chromosomal regions • Environmental determinants

  19. DESIGNS • Classical twin study • Classical twin study with separated MZ twins • Twin family studies • Twin-control studies

  20. Classicaltwinstudy • MZ pairs: • DZ pairs:

  21. DESIGNS • Classical twin study • Classical twin study with separated MZ twins • Twin family studies • Twin-control studies

  22. Is a phenotype genetically determined? • Categorical data • Continous data

  23. Types of concordance • Pairwise: Probabilitythatboth in a pair is affected: • Casewise/probandwise: Probabilitythat a twin is diseased given that the twin partner is diseased:

  24. Probandwise concordance Estimate of the casewiseprobability by the proband method. 2C1 + C2 2C1 + C2 + D • -----------------

  25. Concordance CMZ = CDZ CMZ > CDZ CMZ <1.0 (100%)

  26. Solutions to problems with age at diagnosis • Survival analysis • Actuarial/Kaplan Meier methodology • Frailty models • Newer models • Others? • Correction methods

  27. Concordance type 1 diabetes Zygosity Pairs Concordance (probands) Pairwise* ProbandwiseCumulated Conc Disc MZ 10(18) 16 0.38 0.53 0.70 [0.20-0.59] [0.33-0.73] [0.45-0.95) DZ 4 (8) 65 0.06 0.11 0.13 [0.02-0.14] [0.05-0.21] [0.04-0.21] ( ) Number of probands; [ ] 95% confidence limits. * Chi21d.f. = 10.93, p < 0.001

  28. Cumulativeconcordance type 1 diabetes Interpretable as cumulativerisk from birth % 0-100 MZ 0.70 DZ 0.13 Age 0-40

  29. Correlations • Twin-twincorrelations rMZ= rDZ rMZ> rDZ rMZ< 1.0 (100%)

  30. INTRACLASS CORRELATIONS lnTSH (Pia Skov Hansen) MZ n=284 pairs DZ n=285 pairs rMZ=0.64 (CI 0.56-0.70) rDZ=0.29 (CI 0.18-0.39) p<0.00005

  31. INTRACLASS CORRELATIONS lnTSH

  32. Aetiological components • Additivegeneticvariance • Dominant geneticvariance/epistasis • Common environmentalvariance • Unique environmentalvariance

  33. Inheritance Models in Single Gene Trait

  34. Inheritance Models in Quantitative Trait

  35. Heritability • V (total) = VG + VE • V (total) = VA + VD +VI + VC +VE • h2narrow = VA/VA + VD +VI + VC +VE • h2broad = VA + VD +VI/VA + VD +VI + VC +VE

  36. Heritability • Function of population, NOT a constant • Does not apply to individuals • Biased if mean and variance not the same in MZ and DZ • Greater MZ covariance will inflate h2

  37. Correlations and aetiological models rMZ < 1 rMZ = rDZ = 0 rMZ = rDZ > 0 rMZ = 2rDZ > 0 rMZ > 2rDZ rMZ < 2rDZ

  38. Aetiological models and genetic variation • Varianceanalysis • Regression analysis • Structural equation modelling

  39. Path model for twin analysis

  40. Pleiotrophy

  41. RESULTS TSH-LEVEL Unique Environmental effect 0.36 Genetic effect 0.64 The geneticeffectsaccount for 64% of the variation

  42. Multivariate ACE Model

  43. Important assumptions • Biology of twinning • ”True” zygosity • Equal environment assumption • true or not true? • Generalisability

  44. Adoption studies

  45. Adoption design • Adopteesareexpected to

  46. Early death in adoptees

  47. Assumptions and problems • Early adoption • Non-familial adoption • Comparableenvironment in biological and adoptivefamily • Contact to biologicalfamily • Intra-uterineenvironment • Transcultural adoptions

  48. Comparison of correlations

  49. Comparison heritability

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