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Return to Pedigree Studies

Return to Pedigree Studies. Why GWAS and vGWAS should deploy family-models Dalton Conley NYU & NBER. GREML. G enomic-Related-Matrix Re stricted M aximum L ikelihood: Estimating heritability directly from genome-wide data

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Return to Pedigree Studies

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  1. Return to Pedigree Studies Why GWAS and vGWAS should deploy family-models Dalton Conley NYU & NBER

  2. GREML Genomic-Related-Matrix Restricted Maximum Likelihood: • Estimating heritability directly from genome-wide data • Use genome-wide data to estimate genetic similarity between pairs of unrelated individuals (i.e. summed gametic correlation) • Regress (ML estimation) phenotypic distance against genetic distance

  3. Regression of Height Differences against Genetic Relatedness

  4. Key Identifying Assumption: Among individuals who are unrelated— environmental factors are uncorrelated with differences in their degree of genetic similarity, which itself results from random differences in the recombination and segregation of alleles

  5. Type II Error: Kolmogorov-Smirnov Test (p-value = 7.037e-08)

  6. HRS Analytic Sample: 6,414 ~ 24,030,580 pairs

  7. GREML Results

  8. Sibling IBD

  9. IBD Estimates of Height Heritability

  10. Genetic Risk Scores:Also Confounded?

  11. Framingham Heart Study: Highest Grade Completed

  12. Modeling the error term in GWAS with vGWAS The Search for Phenotypic Stablizers and latent GxE / GxG

  13. Yang et al. 2012: Manhattan Plot FTO RCOR1 -log(pval) Chromosome

  14. A better approach: Family based analysis of sibling standard deviation with controls for parental genotype

  15. Framingham Heart Study: vGWAS of Sibling SD in Height Controls for parental genotype; N= 1573

  16. Is effect an artifact of dominance?

  17. Problems Identified • Focus has been on adequate sample size for genome-wide associations at expense of careful consideration of confounding • GREML key assumption is violated • Future GREML analysis must include robustness checks for co-segregation of environment • Typical population based modeling of vGWAS has no way of untangling mean / variation effects

  18. Alternative Approach • Combine old-fashioned pedigree analysis with new GWAS association studies to create within-family models where genotype is randomized • Using this approach, we can account for both mean& variation genetic effects with complete orthogonality to environment

  19. Thanks! • NYU Bio: Mark Siegal & Siegal Lab; Justin Blau, Richard Bonneau, Tomas Kirchoff& Michael Purugganan • Others: Emily Rauscher, David Cesarini, Chris Dawes, Ben Domingue, Jason Boardman, Patrick Magnusson, Kathleen Harris, Matthew McQueen, OferTchernichovski

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