ANALYTIC STRATEGIES TO DETECT LINKAGE TO A COMMON DISORDER WITH GENETICALLY-DETERMINED AGE-OF-ONSET - DIABETES-MELLITUS IN PIMA-INDIANS

Segregation analysis suggests that the high prevalence of non-insulin- dependent diabetes mellitus in Pima Indians may be partially due to a single locus with a major effect on age of onset. A simulation study w as conducted to evaluate the power of various age-adjustment strategie s in linkage analysis to detect this putative gene in 1,862 sib-pairs from 264 potentially informative nuclear families. Simulations were pe rformed at a recombination fraction (theta) of 0.05 for values of poly morphism information content (PIC) ranging from 0.38 to 1.00. Under th e codominant age-of-onset model supported by segregation analysis, pow er to detect linkage (at P < 0.0001) at PIC = 1.00 was 75% for the Has eman-Elston (HE) sib-pair test and 63% for the affected sib-pair test (ASP) with no age adjustment. Substantial improvements in power were p ossible for the HE test by defining the trait as a survival analysis ' 'residual'' (power = 91%) and for the ASP test by use of an age-of-ons et threshold above which individuals are not included in the analysis (power = 90%, for age of onset < 45 yrs). The parametric method of lin kage analysis was most powerful, as long as both the analysis model an d the simulation model involved a genetic effect on age of onset, rega rdless of whether dominance at the trait locus was misspecified. Metho ds of age adjustment based on the probability of eventually becoming a ffected only improved power when the genetic effect was on susceptibil ity rather than age of onset. The method of age adjustment in linkage analysis may depend on whether one anticipates a genetic effect primar ily on age of onset or on ultimate susceptibility, (C) 1998 Wiley-Liss , Inc.dagger.