Second, linkage (and therefore linkage meta-analysis) failed to detect robust signals because the majority of the actual contributory loci are of modest effect.
Individually the variants are of modest effect (for example, increasing risk from 1 to 1.15) and collectively they account for a small proportion of total variance in risk; findings that are of limited diagnostic or prognostic utility.
There is no doubt that genes other than PRNP contribute to prion disease susceptibility and considerable progress has been made towards their identification, however, in human it is becoming clearer that there may be many common variants but these are of modest effect.
The NOS1AP variant has been estimated to explain up to only 1.5% of QTc variance [ 23], suggesting the need for additional and larger GWA studies with the potential to detect additional common genetic variants, which are likely to be of more modest effect size.
It is clear from these studies that in common with other complex disorders such as Type II diabetes or physiological traits such as height that susceptibility genes detected by whole genome association studies for AD are common (MAF>0.1) and of modest effect (RR<1.3, with APOE being a notable exception).
Most of the confirmed associations within these loci are with common variants, of modest effect, which well-designed GWAS is adequately powered to detect.
With this level of sensitivity, the SNP-MaP approach should be able to detect QTLs of modest effect size if large samples are used.
GWAS have proven to be much more successful than linkage studies, which were underpowered to detect variants of modest effect (2), and candidate gene studies, which are non-systematic and biased due to our limited knowledge of the biological pathways implicated in disease pathogenesis (3).
Essential hypertension (EH) and cardiovascular disease are common, multifactorial disorders likely to be influenced by multiple genes of modest effect.
Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1 5% MAF) and rare (<1%) variants are of great importance.
