THE POWER TO DETECT LINKAGE IN COMPLEX DISEASE BY MEANS OF SIMPLE LOD-SCORE ANALYSES

Maximum-likelihood analysis (via LOD score) provides the most powerful method for finding linkage when the mode of inheritance (MOI) is know n. However, because one must assume an MOI, the application of LOD-sco re analysis to complex disease has been questioned. Although it is kno wn that one can legitimately maximize the maximum LOD score with respe ct to genetic parameters, this approach raises three concerns: (1) mul tiple testing, (2) effect on power to detect linkage, and (3) adequacy of the approximate MOI for the true MOI. We evaluated the power of LO D scores to detect linkage when the true MOI was complex but a LOD sco re analysis assumed simple models. We simulated data from 14 different genetic models, including dominant and recessive at high (80%) and lo w (20%) penetrances, intermediate models, and several additive two-loc us models. We calculated LOD scores by assuming two simple models, dom inant and recessive, each with 50% penetrance, then took the higher of the two LOD scores as the raw test statistic and corrected for multip le tests. We call this test statistic ''MMLS-C.'' We found that the EL ODs for MMLS-C are greater than or equal to 80% of the ELOD under the true model when the ELOD for the true model is greater than or equal t o 3. Similarly, the power to reach a given LOD score was usually great er than or equal to 80% that of the true model, when the power under t he true model was greater than or equal to 60%. These results undersco re that a critical factor in LOD-score analysis is the MOI at the link ed locus, not that of the disease or trait per se. Thus, a limited set of simple genetic models in LOD-score analysis can work well in testi ng for linkage.