Sequencing may be better than genome-wide association studies at finding causal variants in common diseases, according to researchers from Duke University.
The researchers came to this conclusion after performing whole-genome sequencing studies on 29 individuals and finding that rare variants are significantly more likely than common ones to be functional.
Genome-wide association studies have been used to try to pinpoint the genetic underpinnings of common disease, but have so far only been able to explain a small proportion of the predicted heritability. Rather, the Duke study suggests that rare variants, which GWAS so far have not been designed to find, may be responsible for common diseases.
To arrive at their results, researchers in David Goldstein’s lab at Duke sequenced 29 individuals on the Illumina Genome Analyzer to an average 28-fold coverage, and called 5,491,245 single nucleotide variants.
After applying filters to eliminate SNVs inside repeat regions, copy-number variations, segmental duplications, 1 kilobase regions around assembly gaps, and regions aligned to deletions, the team was left with 3,533,186 high-quality SNVs to analyze.
They then separated those variants according to their minor allele-frequency value and analyzed them according to evolutionary conservation, gene structure, or regulatory potential.
For each of the functional categories, the researchers found a significant enrichment of lower-frequency variants and calculated that odds ratios were highest when comparing variants whose minor-allele frequency was less than .052 to all other variants.
“For all the functional categories, when the variants are more rare they are more likely to be in the functional region and therefore more likely to cause phenotypic effect,” said Qianqian Zhu, a co-lead author of the study published in last week’s American Journal of Human Genetics.
The team studied a variety of functional regions for the presence of rare variants, including genes, protein-coding genes, both the 3′ and 5′ untranslated regions, regulatory regions, exons, and introns. They found that for all the regions, rare variants were significantly more enriched than common variants, with odds ratios of up to two. Read more…