Multiple causal genetic variants underlie some qualitative human traits

Some human traits, including those associated with complex inflammatory diseases like multiple sclerosis, Crohn’s disease, and irritable bowel syndrome, are determined by multiple linked genetic variants, according to a new study. What’s more, the study shows that causal effects for these traits may be weaker than previously hypothesized. A major goal of human genetic studies is to identify genetic variants that causally influence human traits, particularly those relevant to human health. Although genome-wide association studies (GWAS) have proven to be a valuable tool to assess the effect of individual genetic variants on specific traits, it remains a challenge to identify a single causal variant among multiple correlated variants. Moreover, mapping quantitative trait loci (QTL) – regions of the genome statistically associated with a specific phenotype – to a causal genetic variant is difficult as most target loci are located in non-coding parts of the genome and are in regions containing multiple, tightly spaced variants. Nevertheless, within these regions, its often assumed that a single casual genetic variant is responsible for a particular phenotype. To better understand how genes link to a phenotype, Nathan Abell and colleagues applied massively parallel reporter assays (MPRA) to targeted regions of the genome to determine links between genetic variants and qualitative human phenotypes. Abell et al. found that at least 17.7% of the regulatory regions evaluated contained more than one causal variant and that the variant effects are often weaker than previously believed, which may suggest that the genetic underpinning of a phenotype may be due to multiple linked causal genetic variants.