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Genetic research designs in the real world

Genetic research designs in the real world Vishwajit L Nimgaonkar MD, PhD University of Pittsburgh nimga@pitt.edu Complex disorders: models of causation Genetic factors : Several genes induce cumulative, small but discrete effects +

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Genetic research designs in the real world

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  1. Genetic research designs in the real world Vishwajit L Nimgaonkar MD, PhD University of Pittsburgh nimga@pitt.edu

  2. Complex disorders: models of causation Genetic factors: Several genes induce cumulative, small but discrete effects + Environmental factors: etiological role / increased variability -No Etiological Factor Necessary or Sufficient -Formal proof dependent on statistical analyses

  3. Factors influencing mapping efforts • What is the phenotype? • What polymorphisms are being used? • What is the study design?

  4. Key phenotype issues • Is the phenotype heritable? • Proportion of risk due to genetic factors? • Proportion of risk due to an individual gene (# genes?) • Familial aggregation does not necessarily prove genetic etiology • Can the phenotype be evaluated reliably?

  5. Discrete Continuous (disease) (liability) 0 1 t What is the phenotype? (L Almasy, PhD)

  6. Phenotypes • Qualitative (diagnostic status) • Clinically relevant • Difficulties in delineating ‘genetic’ phenotype • Quantitative (‘endophenotype’) • Heritable • Differences between cases and controls • Differences between unaffected relatives & controls • Plausible role in pathogenesis, proximate to Dx

  7. What polymorphisms? • Single nucleotide polymorphisms: SNPs • Repeat polymorphisms • Insertions / deletions

  8. What is the study design?

  9. Gene mapping studies: concepts • Examine correlation between genetic variation and trait of interest • Significant correlation establishes genetic etiology

  10. Human genome: 3 billion base pairs (estimated variations = 8,000,000 – 10,000,000) Problems 1. All genetic variations unknown 2. All variants can not be evaluated

  11. Recombination

  12. *Mutation* Haplotype 1 Marker A1 Marker A2 Marker B1 Marker B2 Gene mapping concepts case control

  13. Transmission Of Normal Gene Generations: 1 2 Ill Individual Healthy Individual 3 Transmission Of Disease Gene n Recombination based gene mapping

  14. founder generations Linkage Association Linkage / Association

  15. What is the study design? POSITIONAL CLONING Step 1: Identify large shared chromosomal segments among cases within families (LINKAGE) Step 2: Narrow the shared region using cases and controls (ASSOCIATION).

  16. Linkage: haplotype sharing

  17. Related issues • Ascertainment and recruitment! • Power: more is better! ‘much, much more’ preferred • Design modification • Two stage design (accept lower lod cutoffs) • Covariate based analyses

  18. A,B A,C A,B A,B A,B C,D Linkage: affected sib-pairs (identity by descent) Alleles shared IBD: 2 0 1 0.25 Prevalence: 0.50 0.25

  19. ASP analysis • Convenient design • Concerns • Truncation of family size due to morbidity • ‘True’ sibling recurrence risk • Uncertain paternity • Twinning • Power: n = 400 ASPs; power > 80% for λs = 3.0 (LOD = 3)

  20. Quantitative trait mapping • Quantitative trait analyses • Standard variance component analyses • Multipoint analyses • Sequential search strategies • Epistasis • Multivariate analyses • Bivariate analyses with diagnosis + trait

  21. Sample size required for 80% power to detect linkage to a QTL at a LOD of 3 (Almasy et al.)

  22. Transmission Of Normal Gene Generations: 1 2 Ill Individual Healthy Individual 3 Transmission Of Disease Gene n Associations at the population-level

  23. Factors influencing associations • Sample selection & size • Population history (fitness, drift, migration) • Features of mutations (no, age, frequency) • Features of markers (informativeness, LD) • Number of comparisons • Ethnic admixture

  24. A, B C, D A, C B, D Family based associations (haplotype relative risk) Hypothetical control

  25. Transmission Disequilibrium Test (TDT) A1, A2 A3, A4 A4, A3 A1, A1 A2, A2 A2, A1 A1, A2 A1, A4 A1, A3 Reject Accept Accept

  26. Family based associations • Recruitment expensive • Ascertainment may be biased • Easier than multiplex pedigrees • Power: Issues • Uncertain paternity • Genotyping errors • Power diminishes for case-parent duos

  27. ‘Novel’ designs • Cytogenetic abnormalities • Pooled DNA analyses

  28. Thank you!! • Collaborators: • Laura Almasy, PhD • Bernie Devlin, PhD • Rodeny Go, PhD • Ruben Gur, PhD • Raquel Gur, MD, PhD

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