Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels

Abstract

The level of Factor XII (FXII) is an important phenotype that exhibits a high genetic component and is associated with thrombotic disease. In a genome-wide linkage scan, we demonstrated that the F12 gene represents a quantitative trait locus (QTL) that influences FXII levels. The current study investigated the genetic architecture of the F12 gene to locate polymorphism(s) responsible for the variation of FXII levels. Re-sequencing of the F12 gene in 40 unrelated individuals (selected from the tails of normal distribution of FXII levels) identified 26 polymorphisms which were genotyped in 398 individuals belonging to 21 families from the GAIT Project. By a measured genotype association analysis, eight of 26 SNPs showed significant P-values less than 10(-5) (after multiple test correction) with FXII levels. In addition, the Bayesian Quantitative Trait Nucleotide method, which infers those polymorphisms most likely to have a direct influence on the trait under study, provided evidence that only rs1801020 variation accounted for the variance attributed to this QTL. Moreover, we have analyzed the evolutionary processes that produced the variation in F12 gene and concluded that is evolutionarily neutral and that the T allele of the rs1801020 appeared approximately 100 000 years ago and spread to most human populations rising to high frequencies by genetic drift. Our study provides a template for future genetic studies of human quantitative traits, as we move beyond QTL localization to the polymorphisms responsible for the variation of important biomedical phenotypes.

Ischemic stroke is associated with the ABO locus: The EuroCLOT study

“…We also identified associations between SNPs in the vicinity of the F7 gene and FVII:C, consistent with a number of studies that have previously identified relationships between variation in the structural genes for FVII and circulating levels. 39,40 No other SNPs significantly associated with coagulation intermediate phenotypes were significantly associated with ischemic stroke.…”

Low intraindividual variability of activated partial thromboplastin time revealed in a population of 10 487 control individuals

“…Indeed, it has been known that the levels of certain coagulation proteins are genetically determined. The VWF and F12 loci were reported to represent a quantitative trait locus (QTL) for VWF and FXII levels, respectively [12,13]. The ABO Low intraindividual variability of aPTT Ma et al 747 The distribution of coefficient of variation (CV) values of aPTT in the 10 487 study individuals.…”

The role of large pedigrees in an era of high-throughput sequencing

“…Some of the earliest successful studies of more complex, multilocus traits also started with one or two large pedigrees, with subsequent focus on genes in region(s) with significant evidence of linkage in those pedigrees. These studies include: (1) a variant in affecting plasma adiponectin levels identified as a candidate in a region with linkage evidence (Bowden et al 2010), (2) two studies that also used quantitative trait linkage analysis and followed this with a comprehensive measured genotype approach of all variants in the region identified from sequencing (Musunuru et al 2010; Rosenthal et al 2011), and (3) one study with a focus on a candidate gene, but with comprehensive sequencing and a measured genotype approach to evaluate all variants in the gene (Calafell et al 2010). In these latter studies, the measured genotype approach (Almasy and Blangero 2004) was feasible because of the restricted region of interest: in this context, it is computationally feasible to every variant in a region for its ability to explain the segregating variance.…”