7/31/2023 0 Comments Nature geneticsFollowing multi-ancestry meta-analysis in the discovery phase, a total of 1,465 variants at 25 loci met a genome-wide significance threshold ( P < 5 × 10 −8 Supplementary Figs. Through genotype imputation, we obtained 25.4 million, 40.3 million and 34.9 million DNA sequence variants for analysis in participants of European, African and Hispanic ancestry, respectively (Supplementary Table 1). Participants with TAAD were more likely to be older, male, prescribed statin therapy and former smokers. 1) their baseline characteristics are presented in Supplementary Table 1. The initial MVP discovery analysis was composed of 8,626 individuals (7,050 European, 1,266 African and 310 Hispanic ancestry participants) with TAAD and 453,043 disease-free individuals from the same ancestral groups (Supplementary Fig. Leveraging the MVP resource, we sought to (1) perform a genetic discovery analysis for TAAD across multiple ancestries, (2) explore the spectrum of phenotypes associated with TAAD risk variants through a phenome-wide association study (PheWAS), (3) examine the genetic relationship between TAAD and its epidemiologic risk factors, (4) map causal variants and genes for disease, (5) identify causal tissues and cell types and (6) construct and test a polygenic risk score (PRS) for TAAD (Fig. We recently demonstrated that a VA Healthcare System-based biobank can aid in the genetic discovery of aortic disease 7 and allows for the elucidation of causal biology and mechanisms. The Million Veteran Program (MVP) is a genomic and precision medicine cohort established in 2011 by the Department of VA Healthcare System to study how genes affect health and disease. As a result, most of what is understood about the genetics of TAAD has been derived from studies examining rare, pathogenic variants resulting in heritable aortopathy (so called, hereditary TAAD or ‘HTAAD’) 6. Despite the lethality of these conditions, the genetic determinants of TAAD remain largely unknown, with published GWAS having revealed only four loci reaching genome-wide significance 3, 4, 5. In addition, dissections of the ascending (Stanford type A) or descending (Stanford type B) thoracic aorta are life-threatening conditions requiring emergency treatment, often including surgical repair, and are associated with high short-term and long-term mortality risk 1, 2. Thoracic aortic aneurysms, a dilation of the proximal aorta, are known to progressively enlarge over time, ultimately leading to rupture and death if not surgically repaired. TAAD encompass a spectrum of aortic pathology affecting the aortic root, the ascending aorta, the aortic arch and the descending thoracic aorta. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size. ![]() We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. We identified 21 TAAD risk loci, 17 of which have not been previously reported. ![]() Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |