GRK5 Associated with Thrombin-Induced Platelet Aggregation
Rodriguez et al., p. 211
Anti-platelet therapies are an important intervention during acute cardiovascular events, but the increase in bleeding risk they pose prevents their use as a long-term strategy. Identifying additional targets that could result in milder bleeding risks might allow anti-platelet therapies to be used as a preventative approach. In this issue, Rodriguez et al. identify a non-coding GRK5 variant that is associated with platelet aggregation in response to thrombin and GRK expression. Additionally, this variant is an eQTL for GRK5 expression in multiple platelet datasets, but not in any of the other tissues represented in GTEx, and it appears to disrupt a GATA1-binding site in an enhancer. Taken together, these results suggest a model in which increased GRK5 expression is associated with decreased platelet reactivity. As predicted, the reduction of GRK5 expression in an iPSC-derived megakaryocyte and platelet production model led to increased markers of platelet activation. Platelet activation and clot formation can contribute to cardiovascular and cerebrovascular disease, and indeed, the GRK5 variant appears to be associated with arterial thrombosis, venous thromboembolism, deep venous thrombosis, and pulmonary embolism. Although GRK5 does represent a promising target, it will be important to perform additional work aimed at identifying potential off-target effects and relevant mitigation approaches.
Inclusion of Rare Variants from Diverse Populations Boosts GWAS Interpretation
Kim et al., p. 251
The variation in any given population reflects the demographic history of that population. Shaped by founder and bottleneck events, genetic drift, and isolation, this variation can result in dramatically different genetic architecture. To generate a more complete picture of trait-associated variation in humans, genetic studies must include diverse populations. For example, American Indians experience elevated rates of type 2 diabetes and obesity and have a distinct demographic history driven by both migration and bottleneck events. In this study, Kim et al. characterize coding variants that are associated with metabolic traits in approximately 6,700 Southwestern American Indians (SWAI). When compared to European populations, the SWAI population has fewer predicted loss-of-function (pLOF) variants; however, the variants that are present have risen to higher frequencies. In several GWAS loci that have been associated with metabolic traits in Europeans, SWAI have a gene-burden of pLOF variants, providing further evidence that variants in these genes can contribute to type 2 diabetes, obesity, and lipid traits, for example. Because these variants are rare and could have large effects, unlike most SNPs identified by GWAS, future work to characterize these variants could provide much-needed insights into metabolic function across all populations while also supporting personalized-medicine approaches for SWAI.
Insights into African Roots
Micheletti et al., p. 265
Between the 16th and 19th centuries, the transatlantic slave trade forcibly moved millions of Africans to the Americas. Through the study of shipping records and first-hand accounts, historians have pieced together some of the history of the people whose lives were uprooted during this time period. However, incomplete and missing documentation leaves many questions, including those related to illegal slave trade, unanswered. Advances in genomic technology now allow geneticists to investigate some of these outstanding questions about slaves and their descendants. In a comprehensive analysis of historical documents and genotyping data in this issue, Micheletti et al. report the genetic consequences of centuries of slavery. Much of their work, including geographical connections between areas in the Americas and distinct regions in Africa, agrees with historical records. More interesting, perhaps, are the inconsistencies brought to light by genetics. For example, the authors uncover genetic signatures of the intercolonial slave trade that developed as the transatlantic routes were outlawed in some American countries. Other findings, including those related to sex bias, most likely illustrate societal biases and inhumane treatment of enslaved people. The authors’ work highlights some of the permanent signatures—genetic and societal—from this period of time.
Finding the BEST Gene Therapy
Sinha et al., p. 278
Although gene therapy is often discussed as a single entity, multiple therapeutic approaches fall under the umbrella of gene therapy. An attractive option for disorders caused by a complete or partial loss of protein function is the re-introduction of the wild-type version, an approach referred to as gene augmentation. Treatment of dominant disorders, by contrast, is often envisioned to require gene editing or antisense approaches. In this issue, Sinha et al. assess whether gene augmentation could be considered for the treatment of a dominant maculopathy, BEST disease. This disorder, caused by mutations in BEST1, a gene that encodes a calcium-activated chloride channel, results in progressive and irreversible vision loss. To model BEST disease, the authors generate retinal pigment epithelium (RPE) cells from iPSCs derived from individuals with different BEST1 mutations. Lentiviral transduction of wild-type BEST1 in two of the RPE lines restored BEST1 activity and improved rhodopsin degradation. One RPE line, harboring a mutation located in a different region of BEST1, did not respond; here, the authors demonstrated that gene editing might be a viable alternative. The authors’ work provides support for the idea that gene augmentation can be considered for the treatment of dominant disorders, but it also highlights several important caveats to consider when determining genotype-specific therapeutic strategies.
Confounding Mutations
Tuke et al., p. 325
Mounting evidence supports a model in which somatic variants undergo clonal expansion during the normal aging process. When such mutations rise to high prevalence in the blood—through a process known as clonal hematopoiesis—they can be difficult to distinguish from germline variants. Accordingly, genomic analyses that focus on an aging population could be subject to confounding and subsequent spurious conclusions. Indeed, several genes, when mutated, can underlie developmental disorders in the germline state or promote cancer growth when somatically altered. In this issue, Tuke et al. leverage the scale of the UK Biobank to assess the prevalence of clonal hematopoiesis of large copy-number variants (CNVs), a class of variants associated with a range of phenotypes. Among the many large CNVs identified were aneuploidies known to be incompatible with normal development; the authors conclude that these must have arisen through clonal expansion. Several of these variants have been implicated in cancer, and indeed, the presence of related ICD-10 codes in the accompanying electronic health records supports a higher prevalence of neoplasias and myeloid disorders in individuals who harbor these variants. In total, the authors’ work suggest that care is warranted when interpreting rare variants—of any size—present in population databases. Somatic variants present in adult cohorts should not be used for estimating the penetrance of germline variants in younger populations; careful evaluation of the nature of each variant, including the process by which it arose, is most likely required.