A candidate gene study of F cell levels in sibling pairs using a joint linkage and association analysis

Introduction Fetal haemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and the heritability of FC levels has been estimated to be 89% in the healthy European population; measured genotype analyses have shown the trait to be influenced by several genetic factors. In addition to the β-globin gene complex on chromosome 11p, linkage analyses have reported loci affecting FC levels on chromosomes Xp22.2–p22.3 and 6q23.

Methods We have genotyped a sample of approximately 300 unselected, same sex, dizygotic twin pairs from the St. Thomas’ UK Adult Twin Register for markers in these three regions and carried out a linkage analysis of FC levels. We also used a new method to simultaneously test for linkage and allelic association, and association caused by population stratification or admixture.

Results There was no evidence for linkage of FC levels to chromosomes Xp22.2–p22.3 and 6q23. However, the β-globin cluster was shown to be significantly linked and to be responsible for approximately one-third of the additive genetic variance in FC levels in the sample.

Conclusions The report represents the first application of this method to a sample of nonsimulated data and demonstrates the effectiveness of the approach. Combined linkage and association analysis of the β-globin complex showed a strong association between the XmnI-^Gγ site and FC levels and that the observed association is not an artifact of recent population admixture or stratification.