NEW YORK (GenomeWeb News) – A Wellcome Trust Sanger Institute-led team reported in PLoS Genetics last night that it has come up with a strategy for sifting through genome-wide association study data to narrow in on functionally relevant genetic changes.
"GWA studies have been very successful in allowing us to home in on the biologically relevant parts of the genome," senior author Panos Deloukas, head of the Sanger Institute's genetics of complex traits in humans group, said in a statement, "but we need to build functional data sets in all human cell types to convert initial findings into biological mechanisms."
"This study is one such example and shows the power of integrating genomic and biological data," he added.
Using formaldehyde-assisted isolation of regulatory elements or FAIRE with custom oligonucleotide tiling arrays, the researchers looked at how regulatory element distribution in the genome coincided with dozens of loci previously linked to cardiovascular or blood related traits in two cell types: a megakaryocytic cell line called CHRF-288-11 and the K562 erythroblastoid red blood cell line.
In the process, the team found that a non-coding SNP on chromosome 7 that's associated with platelet volume and function falls in a region with open chromatin in the megakaryocyte cells, which produce platelets, but not in the red blood cells.
Their follow-up experiments — which included targeted Sanger re-sequencing of the open chromatin region of interest in 643 individuals of northern European ancestry, as well as expression and protein interaction studies in mutant mice — indicated that the chromosome 7 variant influences platelet-related traits by altering the binding of EVI1, a transcription factor that mediates the expression of a platelet-related gene called PIK3CG.
Together, researchers explained, the findings support the notion that functionally significant SNPs are apt to turn up in "nucleosome-depleted" parts of the genome with open chromatin — suggesting that it may be useful to focus on such regions when looking for causative changes in GWAS data.
"The intersection of maps of open chromatin with variants identified through GWA studies can facilitate the search for underlying functional variant(s)," they wrote. "We provided evidence that open chromatin profiles exhibit distinct patterns among different cell types and that cell-specific [nucleosome-depleted regions] can be useful in prioritizing regions for further functional analysis."
Based on their findings so far, the team is now using a similar strategy to look for causative variants behind other conditions and diseases, including coronary artery disease.
"We are finding many associations and we need a pathway to identify the functional variants and understand their biological meaning," Sanger researcher Dirk Paul, who was lead author on the new study, said in a statement. "We have shown this is one promising route towards that goal."