A causative linkage between placental hypoxia, pre-eclampsia and misregulation of imprinted genes has been suggested [ 46, 47].
A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature.
Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems.
While a causative linkage between HCMV and systemic lupus erythematosus, systemic sclerosis, diabetes mellitus type 1, and rheumatoid arthritis is suggested by some findings reported by the literature, the overall evidence does not convincingly support this notion.
Validation failure may be due to a lack of true associations between the trait and marker but could also be caused by differences in SNP frequencies, different marker-causative mutation linkage phases, genotype-by-environment interactions or epistasis as well as sample size effects and the way the trait is measured.
It is worth noting that non causative markers in linkage disease with the two disease predisposing loci show an important association which nearly depends on disease predisposing loci as r2.
These variants may be not causative but, possibly, in linkage disequilibrium with the actual disease-causing variants.
However, the alleles identified through GWAS are typically not causative but rather in linkage disequilibrium (LD) with the true causal variants.
If disease risk is largely mediated by rare or private causative variants, then individual linkage studies and conservative meta-analytic approaches may fail to produce findings exceeding standard significance thresholds, even in the presence of substantial heritability and true linkage [4].
