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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.

Original publication

DOI

10.1111/j.1469-1809.2006.00279.x

Type

Journal article

Journal

Ann Hum Genet

Publication Date

11/2006

Volume

70

Pages

965 - 970

Keywords

Alzheimer Disease, Chromosome Mapping, Consanguinity, Female, Genealogy and Heraldry, Genetic Linkage, Homozygote, Humans, Lod Score, Male, Pedigree