Random mutations occur in the RNA genome when reverse transcriptase converts the RNA into DNA; these mutations are not corrected and are passed on in subsequent replication cycles.
However, the probability of replicating the specific QTL detected in the initial GWA will generally be low in subsequent replication studies.
Most of these variants (e.g., single nucleotide polymorphisms, SNPs) are not associated with disease in subsequent replication studies [3], even with well-designed studies using a larger number of subjects.
The association of only one candidate gene, GDF5, was well supported by data from multiple studies and reached genome-wide significance (P < 5 × 10−8) in subsequent replication analysis (6, 7).
This variant also showed statistical significance in subsequent replication stages that consisted of two populations, including 8,053 subjects from the Health2 cohort [ 12] and 23,032 subjects from Japanese population [ 6] (Pcombined = 2.44 × 10−15) (Table 3).
The GWA approach is still limited, however, in that study designs involve predefined stringent selection criteria for which SNPs identified from the initial whole genome scan are going to be analysed in subsequent replication studies, a study design enforced by current genotyping costs.
Slippage error creates a loop in one of the strands that gives rise to an insertion or a deletion in the subsequent replications, depending on the strand specificity (replicating or template strand) of loop formation.
Slippage creates a loop in one of strands that gives rise to an insertion or a deletion in the subsequent replications depending upon if the loop is formed in the replicating strand or in the template strand respectively.
The excessive number of changes results in loss of genetic information and production of largely defective virions in the subsequent replication cycle.
Similar results were obtained in a subsequent replication study (adjusted OR=0.72; P=0.016).
