Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

Abstract

Platelet count is a highly heritable trait with genetic factors responsible for around 80% of the phenotypic variance. We measured platelet count longitudinally in 327 monozygotic and 418 dizygotic twin pairs at 12, 14 and 16 years of age. We also performed a genome-wide linkage scan of these twins and their families in an attempt to localize QTLs that influenced variation in platelet concentrations. Suggestive linkage was observed on chromosome 19q13. 13 -19q13.31 at 12 (LOD ¼ 2.12, P ¼ 0.0009), 14 (LOD ¼ 2.23, P ¼ 0.0007) and 16 (LOD ¼ 1.01, P ¼ 0.016) years of age and multivariate analysis of counts at all three ages increased the LOD to 2.59 (P ¼ 0.0003). A possible candidate in this region is the gene for glycoprotein VI, a receptor involved in platelet aggregation. Smaller linkage peaks were also seen at 2p, 5p, 5q, 10p and 15q. There was little evidence for linkage to the chromosomal regions containing the genes for thrombopoietin (3q27) and the thrombopoietin receptor (1q34), suggesting that polymorphisms in these genes do not contribute substantially to variation in platelet count between healthy individuals.

The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans

“…While we have used a candidate gene approach, systematic, genome-wide searches might uncover loci with stronger effects. Linkage-type studies in mice and humans have detected a series of loci for hematologic indices, [12][13][14][15] with one 15 detecting linkage with MCV near the HMIP locus. High-resolution mapping in heterogeneous stock mice, 16 which has a resolution comparable with linkage disequilibrium mapping studies in humans, found significant peaks at a region The ␤ parameter indicates the strength and direction of HMIP-2 haplotype 2.…”

Fishing for Pleiotropic QTLs in a Polygenic Sea

“…However, in the multivariate setting the situation is not so simple de Andrade et al 1997;Amos et al 2001;Marlow et al 2003;Evans et al 2004). The explanation revolves around the fact that a constant component of a random vector not only has zero variance, but also has zero covariance with every other component.…”

“…Eaves et al (1996) extend these ideas to path models that include a QTL source of variation for the study of siblings. Marlow et al (2003) and Evans et al (2004) deftly employ these models on dyslexia-related variables and longitudinal platelet counts. We would also like to call attention to the earlier work on the EM algorithm for multivariate traits by Iturria & Blangero, (2000) as well as work comparing existing computer algorithms for single trait analysis by de Andrade et al (1999).…”

Calculating Asymptotic Significance Levels of the Constrained Likelihood Ratio Test with Application to Multivariate Genetic Linkage Analysis

“…, where t 1 is a column t-vector of ones (Evans, Zhu et al 2004). This kind of constraint may be reasonable for repeated measures if we believe the gene will have the same effect on all measurements.…”

“…This model has a particularly complex asymptotic distribution. The general consensus seems to be that "this issue warrants further detailed attention" (Marlow, Fisher et al 2003), and, "there is an urgent need to characterize the asymptotic distribution associated with these multivariate tests" (Evans, Zhu et al 2004). In a recent paper, Han and Chang (2008) have challenged the correctness of several relevant results in the literature.…”