SNPs in Multi-Species Conserved Sequences (MCS) as useful markers in association studies: a practical approach

Abstract

Background: Although genes play a key role in many complex diseases, the specific genes involved in most complex diseases remain largely unidentified. Their discovery will hinge on the identification of key sequence variants that are conclusively associated with disease. While much attention has been focused on variants in protein-coding DNA, variants in noncoding regions may also play many important roles in complex disease by altering gene regulation. Since the vast majority of noncoding genomic sequence is of unknown function, this increases the challenge of identifying "functional" variants that cause disease. However, evolutionary conservation can be used as a guide to indicate regions of noncoding or coding DNA that are likely to have biological function, and thus may be more likely to harbor SNP variants with functional consequences. To help bias marker selection in favor of such variants, we devised a process that prioritizes annotated SNPs for genotyping studies based on their location within Multi-species Conserved Sequences (MCSs) and used this process to select SNPs in a region of linkage to a complex disease. This allowed us to evaluate the utility of the chosen SNPs for further association studies. Previously, a region of chromosome 1q43 was linked to Multiple Sclerosis (MS) in a genome-wide screen. We chose annotated SNPs in the region based on location within MCSs (termed MCS-SNPs). We then obtained genotypes for 478 MCS-SNPs in 989 individuals from MS families.

Identification of target sequences for association studies - analysis of the pig <i>FABP3</i> and <i>FABP4</i> loci using comparative genomics methods

“…Finally, such an approach improves the selection of potential candidate sequences for association studies. These conclusions are consistent with a recent report that SNPs in MCSs are useful markers in association studies and can be integrated with the current approaches for studies of genes contributing to complex diseases (McCauley, 2007).…”

Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1q43

“…A MAF of 5% was chosen to provide an acceptable statistical power (about 77%) to detect associations for odds greater than 2.0. A small set of multispecies conserved SNPs (MCSSNP) was selected as described [27] then filtered against the tag SNPs to exclude the redundant markers. This yielded a final set of 1853 inter-population tag SNPs (with a density of about 1 SNP per kilobase), of which 1680 had Illumina validated assays.…”

The pre-mir-27a variant rs895819 may contribute to type 2 diabetes mellitus susceptibility in an Iranian cohort

“…It is widely accepted that SNPs within conserved DNA regions are more likely to have phenotype effects, compared to SNPs within non-conserved regions [23].…”