Evaluating genetic heterogeneity in complex disorders

被引:18
作者
Pal, DK
Greenberg, DA
机构
[1] Columbia Univ, Dept Psychiat, Clin & Genet Epidemiol Unit, Unit 24, New York, NY 10032 USA
[2] Columbia Univ, Joseph Mailman Sch Publ Hlth, Div Stat Genet Biostat Dept, New York, NY 10032 USA
关键词
genetic heterogeneity; complex diseases; admixture test; linkage analysis; ascertainment;
D O I
10.1159/000066195
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Objectives: The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (a) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of a relates to the true proportion of linked families with a complex disorder in a population or dataset. Methods: We simulated a two-locus heterogeneity model and varied genetic parameters, ascertainment scheme and phenocopy frequency. Results: In this model, a is almost always overestimated, by as little as 5% to as much as 60%. The bias is largely attributable to (1) intrafamilial heterogeneity arising from ascertainment of families with many affected members or from analysis of dense pedigrees; (2) low informativeness, which occurs in the presence of reduced penetrance; and (3) differences in the evidence for linkage in linked and unlinked families. This bias is also affected by the analysis phenocopy frequency, but only if the linked locus is dominant and the unlinked locus is recessive. Conclusions: We conclude that, in complex diseases, the Admixture test has greater value in detecting linkage than in estimating the proportion of linked families in a dataset. Copyright (C) 2002 S. Karger AG, Basel.
引用
收藏
页码:216 / 226
页数:11
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