Two new studies highlight the findings of an extensive analysis of exomes, coupled with electronic health records (EHR), which has led to the identification of a number of medically relevant genetic variants in humans. The results are part of DiscovEHR, a comprehensive project where more than 50,000 participants in the U.S. provided blood and DNA samples for genomic analyses, and consented to link the data to their individual EHRs. In the first study, Frederick Dewey et al. analyze the data, finding that individual participants had a median of 21 rare gene variants that were predicted to have lost their function (pLOFs), although several hundred common pLOFs were also identified. Intriguingly, the researchers found that genes that were more sensitive to loss-of-function variation were genes essential to life, cancer-associated genes, and genes associated with autosomal dominant human diseases, compared to genes associated with autosomal recessive disease, drug targets, and olfactory receptors. The data also yielded hundreds of genes that have been partially or fully disabled, which could provide valuable insights into their function in future research. About 3.5% of individuals were found to harbor deleterious variants in 76 clinically relevant genes.
In a separate study, Noura S. Abul-Husn et al. analyzed DiscovEHR data in order to better understand gene variants that contribute to the development of familial hypercholesterolemia (FH). FH is characterized by substantial, lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a much greater risk of premature cardiovascular disease. Among the three known genes - LDLR, PCSK9, and APOB - that are associated with FH, the authors identified 19 variants that can lead to development of the disease. Cholesterol levels, as well as increased risk of developing coronary artery disease, were significantly higher in people with the LDLR variants, the authors report. By surveying matching EHR records, they found that 58% of FH variant carriers were currently prescribed a statin medication, which helps reduce the risk of cardiovascular disease, and yet only 46% of those receiving treatment had cholesterol levels under the target recommended for FH patients. These findings are consistent with previous reports and highlight the undertreatment of FH, the authors conclude. These two studies are highlighted in a Perspective by Daniel Rader and Scott Damrauer.