Comparison of Haseman-Elston regression analyses using single, summary, and longitudinal measures of systolic blood pressure

Abstract

To compare different strategies for linkage analyses of longitudinal quantitative trait measures, we applied the "revisited" Haseman-Elston (RHE) regression model (the cross product of centered sib-pair trait values is regressed on expected identical-by-descent allele sharing) to cross-sectional, summary, and repeated measurements of systolic blood pressure (SBP) values in replicate 34, randomly selected from the Genetic Analysis Workshop 13 simulated data. RHE linkage scans were performed without knowledge of the generating model using the following phenotypes derived from untreated SBP measurements: the first, the last, the mean, the ratio of the change between the first and last over time, and the estimated linear regression slope coefficient. Estimates of allele sharing in sibling pairs were obtained from the complete genotype data of Cohorts 1 and 2, but linkage analyses were restricted to the five visits of Cohort 2 siblings. Evidence for linkage was suggestive (p < 0.001) at markers neighboring SBP genes Gb35, Gs10, and Gs12, but weaker signals (p < 0.01) were obtained at markers mapping close to Gb34 and Gs11. Linkage to baseline genes Gb34 and Gb35 was best detected using the first SBP measurement, whereas linkage to slope genes Gs10-12 was best detected using the last or mean SBP value. At markers on chromosomes 13 and 21 displaying strongest linkage signals, marginal RHE-type models including repeated SBP measures were fit to test for overall and time-dependent genetic effects. These analyses assumed independent sib pairs and employed generalized estimating equations (GEE) with a first-order autoregressive working correlation structure to adjust for serial correlation present among repeated observations from the same sibling pair.