Detection and replication of linkage to a complex human disease.
Efforts to map susceptibility loci for complex human diseases frequently result in weak evidence for linkage, followed by failures to convincingly replicate. If a disease locus influences both affection status (AF) and a quantitative trait, a variant of the extreme discordant sib pair (EDSP) strategy may be used to judiciously sample families for a replication study. This approach was evaluated by conducting joint segregation and linkage analysis of four bivariate phenotypes, each comprising AF and one quantitative trait (Q2, Q3, Q4, Q5), and undertaking a genomic scan of the GAW10 Problem 2B data set. Suggestive evidence was found for linkage of AF/Q2 to marker D8G26 (lod = 1.63, chi 2 = 7.52, p = 3.05 x 10(-3)). Sets of 23 EDSP families were selected based on Q2 values that demarcated the bottom 1%, 2%, 5%, 10%, or 20% of the distribution. Highly significant evidence for linkage was found when the 1% or 2% cutoffs were used (lod > 4, chi 2 > 20, p < 4 x 10(-6)), but more than 1,000 families had to be screened. Significant evidence for linkage (lod = 3.24, chi 2 = 14.91, p = 5.63 x 10(-5)) was found in the EDSP sample obtained using a 5% cutoff: about 300 families had to be screened. Only suggestive evidence for linkage (lod = 1.65, chi 2 = 7.59, p = 2.93 x 10(-3)) was found in non-EDSP families. Use of EDSP sampling variants can permit convincing replications not otherwise obtainable in the genetic analysis of complex diseases.
Moldin
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Genetics Research Branch, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland 20857, USA.
D002874:Chromosome Mapping; D003198:Computer Simulation; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008540:Meiosis / Q000235:genetics; D015999:Multivariate Analysis; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D012307:Risk Factors