Abstract
Like cartographers of old who ended up altering the shapes of large land masses to accommodate information from increasingly detailed surveys, genomic scientists are revising their ideas about the respective roles of common and rare genetic variants in complex disease processes. To date, thousands of common variants have been identified by means of genome-wide association studies (GWASs). But these variants are no longer expected to support the simple common disease/common variant (CDCV) hypothesis.
Genomic scientists have observed that the loci detected by GWASs explain little of inferred genetic variance. In light of this “missing heritability” problem, the scientists have moved on. Increasingly, they are looking to reconcile a couple of different views—first: disease risk can be attributed to a large number of small-effect common variants (the infinitesimal view); second: a large number of large-effect rare variants (the rare allele view).
As part of this broad effort to redraw the genomic map of disease susceptibility, researchers at the Montreal Heart Institute (MHI) have been weighing data from GWASs, deep DNA resequencing studies, and exome-wide genotyping. Most recently, they have uncovered findings that suggest these approaches can complement each other in defining the allelic architecture of complex traits. At least, they have demonstrated that this appears to be the case with hematological traits.
The MHI researchers organized an international collaboration that identified a dozen mutations in the human genome that are involved in significant changes in complete blood counts and that explain the onset of sometimes severe biological disorders. These researchers, led by Guillaume Lettre, Ph.D., an assistant professor of medicine at the Montreal Heart Institute and the Université de Montréal, published their finding April 28 in Nature Genetics, in an article entitled “Rare and low-frequency coding variants in CXCR2and other genes are associated with hematological traits.”
“Complete blood counts are a complex human trait, as the number of cells in the blood is controlled by our environment and the combined expression of many genes in our DNA,” explained Dr. Lettre. Moreover, as noted by the authors of the Nature Genetics article, the proliferation and differentiation of hematopoietic progenitor cells into mature blood cells is a tightly regulated process.
“Interindividual variation in quantitative blood cell traits is heritable, and GWASs have implicated hundreds of loci,” they wrote. “The development of new genotyping arrays that target protein-coding variation offers new opportunities to assess the role of rare and low-frequency coding variants in human complex trait genetics.”
In collaboration with their colleagues at the University of Washington in Seattle and the University of Greifswald in Germany, the MHI researchers analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts, and platelet counts in 31,340 individuals genotypes on an exome array. Specifically, they looked at segments of DNA directly involved in protein function in the body.
They researchers identified a significant mutation in the gene that encodes erythropoietin, a hormone that controls the production of red blood cells. “Subjects who carry this mutation in their DNA have reduced hemoglobin levels and a 70% greater chance of developing anemia,” explained Dr. Lettre. The scientists also identified a mutation in the JAK2gene, which is responsible for a 50% increase in platelet counts and, in certain cases, for the onset of bone marrow diseases that can lead to leukemia.
“Our results clearly demonstrate that rare and low-frequency coding variants contribute to phenotypic variation in human populations,” asserted the study's authors. “We discovered new missense variants in key regulators of hematopoiesis (EPO, SH2B3, and TUBB1) that have potential implications for diagnostic screening and drug development in a variety of hematological and inflammatory disorders (cytopenias, myeloproliferative neoplasms, lung disease, and stroke).”
In addition, the authors noted that the association of a collection of rare and low-frequency CXCR2 coding variants with WBC count “emphasizes the relevance of gene-based tests as we continue to query even rarer variants for their role in human phenotypic variation.” They also concluded that “exome arrays complement GWASs in identifying new variants that contribute to complex human traits.”
Dr. Lettre expressed optimism that that the experimental approach used in the current study can be applied to other human diseases. “Thanks to the existing genetic data and wealth of other clinical information available from the MHI Biobank, we will be able to identify other rare genetic variations that may impact the risk of cardiovascular disease and open the door to the development of new therapies.”