Ignoring distant genealogic loops leads to false-positives in homozygosity mapping

Ann Hum Genet. 2006 Nov;70(Pt 6):965-70. doi: 10.1111/j.1469-1809.2006.00279.x.

Abstract

Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Chromosome Mapping / methods*
  • Consanguinity
  • Female
  • Genealogy and Heraldry*
  • Genetic Linkage
  • Homozygote*
  • Humans
  • Lod Score
  • Male
  • Pedigree