This hypothesis predicts that cold regions with segmental duplications should be enriched for structural variants and that multiple independent variants should arise over short evolutionary times.
Based on Mendelian disorders, we have rarely observed multiple independent variants alter the strength of the same splice site, and in any case, the phase of these variants is unknown, so they could reside on different chromosomes.
However, DYX2 has repeatedly shown strong linkage to RD, a pattern generally indicative of one or two variants of large effect, and not of multiple independent variants with more modest effect sizes.
These analyses are also more permissive to locus heterogeneity, where multiple independent variants within a locus have independent effects on a trait (Christoforou et al. 2012a; Yang et al. 2012), and they use prior biological knowledge, facilitating a more meaningful interpretation of data (Wang et al. 2010).
"How does Veridical decide which sequence variant is causative if there are multiple variations located in the vicinity of a given mis-spliced exon?" Veridical does not currently address cases in which multiple independent variants pertain to the same splice site.
Only five of these had previously been identified as containing multiple independent variants (Chr3p12, Chr4q22, Chr8p21, Chr11q13 and Chr17q12); however, our analysis helped to further refine these five regions and identified one additional previously unknown hit at Chr17q12 within the promoter region of HNF1B.
We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions.
To make the situation more complicated, sometimes, a single locus can contain multiple independent risk variants (common or rare).
Analyses for all SNPs were repeated adjusting for the most significant SNP to assess whether multiple independent causal variants were present (i.e. a forward stepwise regression approach).
Until recently, few GWAS had performed conditional and multivariable analyses to test the possibility that multiple independent common variants at a locus were associated with a trait.
Instead of searching for a single locus, multiple independent DNA variants are being selected to identify those responsible for the occurrence of a disease [ 2].
