Estimation of genotype relative risks from pedigree data by retrospective likelihoods

Daniel J. Schaid, Shannon K. McDonnell, Shaun M. Riska, Erin E. Carlson, Stephen N. Thibodeau

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Pedigrees collected for linkage studies are a valuable resource that could be used to estimate genetic relative risks (RRs) for genetic variants recently discovered in case-control genome wide association studies. To estimate RRs from highly ascertained pedigrees, a pedigree "retrospective likelihood" can be used, which adjusts for ascertainment by conditioning on the phenotypes of pedigree members. We explore a variety of approaches to compute the retrospective likelihood, and illustrate a Newton-Raphson method that is computationally efficient particularly for single nucleotide polymorphisms (SNPs) modeled as log-additive effect of alleles on the RR. We also illustrate, by simulations, that a naïve "composite likelihood" method that can lead to biased RR estimates, mainly by not conditioning on the ascertainment process - or as we propose - the disease status of all pedigree members. Applications of the retrospective likelihood to pedigrees collected for a prostate cancer linkage study and recently reported risk-SNPs illustrate the utility of our methods, with results showing that the RRs estimated from the highly ascertained pedigrees are consistent with odds ratios estimated in case-control studies. We also evaluate the potential impact of residual correlations of disease risk among family members due to shared unmeasured risk factors (genetic or environmental) by allowing for a random baseline risk parameter. When modeling only the affected family members in our data, there was little evidence for heterogeneity in baseline risks across families.

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalGenetic epidemiology
Volume34
Issue number4
DOIs
StatePublished - May 2010

Keywords

  • Ascertainment
  • Bias
  • Composite likelihood
  • Gene-dropping
  • Linkage
  • Prostate cancer
  • Relative risk

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

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