Showing papers by "Chao Xing published in 2006"

Genome-wide linkage study of retinal vessel diameters in the Beaver Dam Eye Study

Abstract: Retinal vessels can be observed noninvasively and provide a window to microvascular systems elsewhere in the body. Generalized retinal arteriolar narrowing can represent structural changes resulting from persistent high blood pressure. However, data from recent studies also suggest that generalized retinal arteriolar narrowing might precede hypertension and contribute to its pathogenesis. To determine whether vessel diameters in the eye are genetically determined, we conducted a genome-wide linkage scan on retinal vessel diameters (central retinal artery equivalent and central retinal vein equivalent) using data from the Beaver Dam Eye Study. There were 7 regions on 5 chromosomes (3q28, 5q35, 7q21, 7q32, 11q14, 11q24, and 17q11) showing linkage signals at the nominal multipoint significance level of 0.01 for either covariate-unadjusted or -adjusted central retinal artery equivalent; there were 7 regions on 6 chromosomes (1p36, 6p25, 6q14, 8q21, 11p15, 13q34, and 14q21) showing linkage signals at the nominal multipoint significance level of 0.01 for either covariate-unadjusted or -adjusted central retinal vein equivalent. The linkage results for retinal vessel diameters indicate genetic contributions that remain significant even after adjusting for hypertension and other covariates. In summary, we provide evidence demonstrating that genetic factors independent of hypertension affect retinal vessel diameters.

Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans

Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity. Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis. Using densely spaced microsatellite markers in the linkage region, we have localized the potential SLE susceptibility gene(s) to be telomeric to the marker D4S2928 by haplotype construction. In addition, marker D4S394 showed marginal evidence of linkage disequilibrium with the putative disease locus by the transmission disequilibrium test and significant evidence of association using a family-based association approach as implemented in the program ASSOC. We also performed both two-point and multipoint model-based analyses to characterize the genetic model of the potential SLE susceptibility gene(s), and the lod scores both maximized under a recessive model with penetrances of 0.8. Finally, we performed a genome-wide scan of the total 153 EA pedigrees and evaluated the possibility of interaction between linkage signals at 4p16 and other regions in the genome. Fourteen regions on 11 chromosomes (1q24, 1q42, 2p11, 2q32, 3p14.2, 4p16, 5p15, 7p21, 8p22, 10q22, 12p11, 12q24, 14q12, 19q13) showed evidence of linkage, among which, signals at 2p11, 12q24 and 19q13 also showed evidence of interaction with that at 4p16. These results provide important additional information about the SLE linkage effect at 4p16 and offer a unique approach to uncovering susceptibility loci involved in complex human diseases.

Distribution and magnitude of type I error of model‐based multipoint lod scores: implications for multipoint mod scores

Abstract: The multipoint lod score and mod score methods have been advocated for their superior power in detecting linkage. However, little has been done to determine the distribution of multipoint lod scores or to examine the properties of mod scores. In this paper we study the distribution of multipoint lod scores both analytically and by simulation. We also study by simulation the distribution of maximum multipoint lod scores when maximized over different penetrance models. The multipoint lod score is approximately normally distributed with mean and variance that depend on marker informativity, marker density, specified genetic model, number of pedigrees, pedigree structure, and pattern of affection status. When the multipoint lod scores are maximized over a set of assumed penetrances models, an excess of false positive indications of linkage appear under dominant analysis models with low penetrances and under recessive analysis models with high penetrances. Therefore, caution should be taken in interpreting results when employing multipoint lod score and mod score approaches, in particular when inferring the level of linkage significance and the mode of inheritance of a trait.

The Affected-/Discordant-Sib-Pair Design Can Guarantee Validity of Multipoint Model-Free Linkage Analysis of Incomplete Pedigrees When There Is Marker-Marker Disequilibrium

Abstract: Genomewide linkage studies are tending toward the use of single-nucleotide polymorphisms (SNPs) as the markers of choice. However, linkage disequilibrium (LD) between tightly linked SNPs violates the fundamental assumption of linkage equilibrium (LE) between markers that underlies most multipoint calculation algorithms currently available, and this leads to inflated affected-relative-pair allele-sharing statistics when founders' multilocus genotypes are unknown. In this study, we investigate the impact that the degree of LD, marker allele frequency, and association type have on estimating the probabilities of sharing alleles identical by descent in multipoint calculations and hence on type I error rates of different sib-pair linkage approaches that assume LE. We show that marker-marker LD does not inflate type I error rates of affected sib pair (ASP) statistics in the whole parameter space, and that, in any case, discordant sib pairs (DSPs) can be used to control for marker-marker LD in ASPs. We advocate the ASP/DSP design with appropriate sib-pair statistics that test the difference in allele sharing between ASPs and DSPs.