Using ancestry matching to combine family-based and unrelated samples for genome-wide association studies

Stat Med. 2010 Dec 10;29(28):2932-45. doi: 10.1002/sim.4057.

Abstract

We propose a method to analyze family-based samples together with unrelated cases and controls. The method builds on the idea of matched case-control analysis using conditional logistic regression (CLR). For each trio within the family, a case (the proband) and matched pseudo-controls are constructed, based upon the transmitted and untransmitted alleles. Unrelated controls, matched by genetic ancestry, supplement the sample of pseudo-controls; likewise unrelated cases are also paired with genetically matched controls. Within each matched stratum, the case genotype is contrasted with control/pseudo-control genotypes via CLR, using a method we call matched-CLR (mCLR). Eigenanalysis of numerous SNP genotypes provides a tool for mapping genetic ancestry. The result of such an analysis can be thought of as a multidimensional map, or eigenmap, in which the relative genetic similarities and differences amongst individuals is encoded in the map. Once constructed, new individuals can be projected onto the ancestry map based on their genotypes. Successful differentiation of individuals of distinct ancestry depends on having a diverse, yet representative sample from which to construct the ancestry map. Once samples are well-matched, mCLR yields comparable power to competing methods while ensuring excellent control over Type I error.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biostatistics / methods*
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Family
  • Female
  • Genome-Wide Association Study / statistics & numerical data*
  • HLA Antigens / genetics
  • Humans
  • Logistic Models
  • Male
  • Models, Statistical
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Racial Groups / genetics
  • Racial Groups / statistics & numerical data

Substances

  • HLA Antigens