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Nicholas L Smith

Publications and source records attributed to Nicholas L Smith.

4 recordsLinked to original sources
PubMed2025

Historical review: more than two decades understanding the genetic architecture of hemostasis and thrombosis.

From the beginning of the millennium and the development of genome-wide analyses, the technical advances and remarkable increase in research sample sizes have led to an escalating number of discoveries revealing genetic determinants of levels of the main factors regulating hemostasis and thrombosis and demonstrating a clear polygenic complex regulation of most coagulation factors. These discoveries have been useful to understand the biology underlying hemostasis regulation and to understand risk of associated thrombotic disease, such as venous thromboembolism, coronary artery disease, and ischemic stroke. In this historical review, we outline the main discoveries in genetic studies of coagulation factors (fibrinogen and its alternatively spliced γ' isoform, D-dimer, factor [F]V, FVII, FVIII, von Willebrand factor, and FXI), the main natural anticoagulants (protein C, protein S, and antithrombin), components of fibrinolysis (tissue plasminogen activator and plasminogen activator inhibitor-1), and global coagulation tests (prothrombin time and activated partial thromboplastin time). We explore the clinical implications of these discoveries and suggest new avenues for future investigation.

Humans↗
PubMed2025

Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish.

Venous thromboembolisms (VTEs) are a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. In this study, we employed a genome-wide association study (GWAS) for VTE across 9 international cohorts of the Global Biobank Meta-Analysis Initiative to address this question, along with in vivo functional validation. In this multipopulation GWAS (VTE cases, 27 987; controls, 1 035 290), 38 genome-wide significant loci were identified, 4 of which were potentially novel. For each autosomal locus, we performed gene prioritization using 7 independent, yet converging, lines of evidence. Through prioritization, we identified genes associated with VTE through GWAS and/or functional studies (eg, F5, F11, VWF, STAB2, PLCG2, TC2N), functionally validated those that did not have evidence other than GWAS (TC2N, TSPAN15), and discovered 1 not previously associated with coagulation (RASIP1). We evaluated the function of 6 prioritized genes with strong genetic evidence, including F7 as a positive control, using laser-mediated endothelial injury to induce thrombosis in zebrafish after CRISPR/Cas9 knockdown. From this assay, we have supportive evidence for the role of RASIP1 and TC2N in the modification of human VTE and suggestive evidence for STAB2 and TSPAN15. This study expands on the currently identified genomic architecture of VTE through biobank-based, multipopulation GWASs, in silico candidate gene predictions, and in vivo functional follow-up of candidate genes.

Zebrafish↗
PubMed2025

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (&#x2264; 50 IU/dL) in the general population is underexplored. OBJECTIVES: To identify genetic variants influencing VWF:Ag levels &#x2264; 50 IU/dL. METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels &#x2264; 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS: Variants at 2 loci were associated (P < 5 &#xd7; 10-9) with VWF:Ag levels &#x2264; 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels &#x2264; 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels &#x2264; 50 IU/dL, bleeding, and VWD.

Humans↗
PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗