In this respect it appears that I-03, which has virtually no effect in any of the African-descended populations, is unlikely to be a causative variant.
However, none of the synonymous variants were associated with UC in the Canadian samples, and we observed opposite rs224222 allele association with UC in the Belgian and Canadian cohorts, suggesting that rs224222 was unlikely to be a causative variant contributing to UC susceptibility.
The similarity in frequency of the 5-marker haplotypes associated with height in the VB and NB cohorts, and the identity of the haplotype over a region of more than 20 kb, including 29 SNPs, suggests that if there is a causative variant that is shared between populations, it is relatively infrequent (<10%) and located downstream of the first intron.
Most individuals affected with OI are heterozygous for a causative variant in either of the two genes, COL1A1 or COL1A2, which encode the pro α1(I) and pro α2(I) chains of type I procollagen, respectively.
Without haplotype analyses and functional studies it remains unknown whether rs3738919 is itself a disease-modifying variant or whether it is a signpost for a causative variant that has yet to be discovered.
In the diagnostic setting, it is critical to assess which regions of a gene were adequately interrogated by the test, so that clinicians can determine if additional sequencing is required to detect a causative variant in that gene.
In other words, if a causative variant is removed by LD-based pruning, it will be replaced by another SNP that is closely associated with the causal variant.
Using a whole exome platform, not every gene is perfectly sequenced (i.e. 'covered'), but the breadth is so great that there is a good chance of detecting a causative variant.
Therefore, these polymorphisms do not affect the amino acid sequence of the transmembrane and cytoplasmic subunits unless there is a strong linkage disequilibrium with a causative variant in an exon; nevertheless, it is possible they affect the structure of mature GABAB2 mRNA through alternate splicing, resulting in altered GABAB2 protein subunits.
Our results therefore suggest that chromosomal region around rs2275565 and rs1805087 is a candidate for harboring a causative variant for the survival effect by MTR.
Given O = 1 or 0, we simulate quantitative measure p from the Uniform distribution U a, 1) or U 0, a), where a is the threshold to declare a causative variant.
