A robust multipoint linkage statistic (tlod) for mapping complex trait loci

Classical parametric two-point linkage analysis is a powerful analysis tool , however there are clear disadvantages too, including the sensitivity to a llele frequency misspecification. Conversely, multipoint linkage analysis i s not sensitive to allele frequency misspecification, but it is sensitive t o genetic model misspecification. Going and Terwilliger [Am J Hum Genet 66: 1095-106, 2000] proposed a new robust multipoint statistic that increased t he robustness of multipoint analyses. In this paper we have referred to thi s new statistic as the tld. We applied this new statistic to the Genetic An alysis Workshop (GAW) 12 data using affected status (AFF) as the phenotype of interest. The heterogeneity tlod and two-point hlod scores correlated hi ghly across the genome (p < 0.0001), as expected, but the het-tlod had a lo wer number false positives. In addition, the tlod analysis handled missing data better, as would be expected for a multipoint method. When one-third o f the genotype data was removed (dead people) the tlod analysis was less af fected than the two-point analysis. When tlod scores were compared with mul tipoint lod scores in true gene locations, the robustness of the tlod to mo del misspecification was clearly evident. When the "best" replicate from th e general population was analyzed, a borderline genome-wide significant two -point hlod result (3.6) was found 4 cM from MG6 and MG7 on chromosome 6. T he heterogeneity tlod score was lower than the two-point hlod score (1.8), but greater than the heterogeneity multipoint lod score (0.4). However, whe n replicate I of the isolated population was analyzed none of the true gene locations were identified with either statistic. (C) 2001 Wiley-Liss, Inc.