Evaluating genetic heterogeneity in complex disorders.
OBJECTIVE
The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (alpha) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of alpha 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, alpha 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.
Pal
Deb K
DK
Department of Psychiatry, Joseph Mailman School of Public Health, Columbia University, New York, NY 10032, USA. dkp28@columbia.edu
Greenberg
David A
DA
D005190:Family; D005787:Gene Frequency / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008957:Models, Genetic; D019683:Penetrance