title: Ignoring distant genealogic loops leads to false-positives in homozygosity mapping.
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.
authors.affiliation: Department of Epidemiology & Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Elefante
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Y S
authors.initials: YS
authors.lastname: Aulchenko
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods*; D003241:Consanguinity; D005260:Female; D005789:Genealogy and Heraldry; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree