Evaluating Genetic Heterogeneity in Complex Disorders

TY - JOUR

T1 - Evaluating Genetic Heterogeneity in Complex Disorders

AU - Pal, Deb K

AU - Greenberg, David A

N1 - Copyright 2002 S. Karger AG, Basel

PY - 2002/11

Y1 - 2002/11

N2 - 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 (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.

AB - 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 (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.

KW - Family

KW - Gene Frequency

KW - Genetic Diseases, Inborn

KW - Genetic Heterogeneity

KW - Genetic Linkage

KW - Humans

KW - Lod Score

KW - Models, Genetic

KW - Penetrance

U2 - 10.1159/000066195

DO - 10.1159/000066195

M3 - Article

C2 - 12435885

SN - 0001-5652

VL - 53

SP - 216

EP - 226

JO - Human Heredity

JF - Human Heredity

IS - 4

ER -