Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity.
Some investigators have expressed concern--especially for psychiatric disorders--that bilineal pedigrees should not be included in linkage studies. This study compares the "informativeness" of bilineal and unilineal families for a homogeneous single-gene disorder. Three approaches were used: (1) simulation studies of three-generation pedigrees, (2) calculation of expected lod scores (ELODs) in nuclear families, and (3) calculation of Fisher's information number I(theta) in nuclear families. The simulation studies in (1) permitted a realistic comparison between bilineal datasets and purely unilineal ones. The calculations in nuclear families in (2) and (3) then made it possible to analyze the sources of information loss in bilineal families. Overall, in datasets of five three-generation pedigrees each, the drop in mean maximum lod score was approximately 50% from purely unilineal datasets to extremely bilineal ones. In less-extreme bilineal datasets, which are closer to most real data than the extremely bilineal ones, the drops in lod score were very small--less than 10% in some, and practically zero in others. The details will vary, depending on size and structure of the pedigree, genetic model, true value of the recombination fraction, and informativeness of the marker. However, these results imply that the information loss due to bilineality is not necessarily very great. The nuclear-family calculations showed that for phase-known matings there is relatively little information loss in bilineal families, but for phase-unknown matings there the loss is much greater. In conclusion, for single-gene disorders with no genetic heterogeneity, whereas bilineal families can be less informative than comparable unilineal families, they are not so much less informative that they should automatically be discarded from linkage datasets. The implications of bilineal pedigrees for linkage studies of heterogeneous disorders are also discussed.
Hodge
S E
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Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
D003198:Computer Simulation; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D008957:Models, Genetic; D010375:Pedigree