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Genome - U.S. Department of Veterans Affairs

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Last Updated: 03 September 2022

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Correction of Fanconi Anemia Mutations Using Digital Genome Engineering.

Fanconi anemia is a rare genetic disorder in which genes essential for DNA repair are changed. Both the interstrand crosslink and double-strand break repair pathways are disrupted in FA, contributing to patient bone marrow failure and cancer predisposition. Here, we demonstrate the correction of FANCA mutations in primary patient cells with the cytosine and adenine base editors. These Cas9-based tools enable C:G > T:A, A:T, or A:C:G base transitions without the introduction of a hazardous DSB or the need for a DNA donor molecule. During autologous HSC gene therapy, this BE digital correction scheme will allow the use of gene-corrected FA patient hematopoietic stem and progenitor cells for autologous HCT, minimizing the risks associated with allogeneic HCT and DSB gene therapy.

Source link: https://doi.org/10.3390/ijms23158416


Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

In which current studies are combined with data from cohorts of white, Black, and Hispanic individuals from the Million Veteran Program, we present a genome-wide association study of coronary artery disease involving nearly a quarter of a million patients. Moreover, we find 15 loci of gene-wide significance that consistently match established loci for clinical CAD in the largest GWAS for angiographically derived coronary atherosclerosis published to date. Improved blood test scores with novel loci and polygenic risk scores, increase signals related to insulin resistance, expand pleiotropic links of these loci to include smoking and family history, and specifically point to the significantly reduced transferability of existing PRS to Black people. Downstream integrative studies support the fundamental roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but they also point to a shared biology of atherosclerosis and oncogenesis.

Source link: https://doi.org/10.1038/s41591-022-01891-3


Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.

Sju00f6gren's disease is a multi-autoimmune disorder with twelve recognized susceptibility loci. Polygenic risk scores yield predictability and relative risk of 12. 08 predictability and relative risk of 12. 08. Many GWS SNPs are eQTLs for genes within topologically related domains of immune cells and/or eqTLs in the key target organ, salivary glands.

Source link: https://doi.org/10.1038/s41467-022-30773-y


A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study.

Obstructive heart abnormalities are present in arteries and cardiac valves, accounting for 25% of all congenital heart abnormalities. In infants and mothers separately, a genome-wide association survey was conducted in National Birth Defect Prevention Study participants, looking at the genetic structure of OHDs in the context of complete case-parental triples and case-control analyses separately. The SLC44A2 single nucleotide polymorphism rs2360743 was highly associated with OHD in the TDT study. In only the study sample, two other SNPs were positively associated with OHD.

Source link: https://doi.org/10.1002/ajmg.a.62759


A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

We did a genome-wide association review of suicide attempts among veterans in a large, multi-ancestry cohort of U. S. veterans enrolled in the Million Veterans Program to determine pan-ancestry and ancestry-specific loci that are connected with suicide among veterans. Veterans with a documented history of suicide attempts in the electronic health record and controls were classified as veterans with no documented history of suicidal thoughts or behaviors in the EHR. Pan-ancestry risk loci were analyzed through meta-analysis, revealing two genome-wide significant loci on chromosomes 20 and 1. In a large, international civilian cohort, the Dopamine Receptor D2 locus was also found and subsequently imitated. These results show that the genetic architecture underlying suicide attempt risk is complicated, with both pan-ancestry and ancestry-specific risk loci included in this study.

Source link: https://doi.org/10.1038/s41380-022-01472-3


Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.

coronary artery disease and peripheral artery disease have common risk factors and have shared pathobiology, affecting different arterial regions, arterial artery disease and peripheral artery disease. We perform 15 novel pleiotropic loci that have not yet reported as genome-wide important for their respective characteristics using summary results from nine well-known atherosclerotic and atherosclerosis risk factors. The signal between PAD and LDL-C at the PCSK6 locus, however, plays a role in human liver tissue splicing and proliferation of pluripotent-like cells, according to commentator (6).

Source link: https://doi.org/10.3389/fgene.2021.787545


Genome-wide meta-analysis of alcohol use disorder in East Asians.

Alcohol use disorder is the most common cause of death and disability worldwide. 30 AUD risk genes have been found in European populations, but not so many in East Asians. The Million Veteran Program sample conducted an GWAS and genome-wide meta-analysis of AUD in 13,551 people with East Asian originstry; DSM-IV diagnosed alcohol dependence in a Han Chinese-Cyto cohort; and two AD Thai cohorts; and two AD Thai cohorts. In an independent survey of 4464 East Asians, an AUD polygenic risk score was determined. Ever vs. never smoking revealed a significant relationship with days per week of alcohol intake and nominally associated with pack years of smoking and is now associated with pack years of smoking. To date, this is the highest GWAS of AUD in East Asians.

Source link: https://doi.org/10.1038/s41386-022-01265-w


The power of genetic diversity in genome-wide association studies of lipids.

Increasing blood lipid levels are hereditable risk factors of cardiovascular disease with varying prevalence worldwide due to different diet habits and medication use1. Blood lipid measurements, as well as new drug targets for cardiovascular disease have all contributed to important biological and clinical findings, as well as new cardiovascular disease prevention methods. However, most recent GWAS4-23 research has been conducted in European ancestry groups, and it may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. We discover that increasing diversity rather than analyzing additional individuals of European ancestry has resulted in significant increases in fine-mapping functional variants and portability of polygenic prediction. We predict that increased diversity of participants in clinical practice will lead to more accurate and equitable26 application of polygenic scores.

Source link: https://doi.org/10.1038/s41586-021-04064-3

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions