We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
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http://dx.doi.org/10.1093/brain/awz024 | DOI Listing |
J Biomed Opt
December 2024
University of Michigan, Department of Biomedical Engineering, Ann Arbor, Michigan, United States.
Significance: Alzheimer's disease (AD) is a predominant form of dementia that can lead to a decline in the quality of life and mortality. The understanding of the pathological changes requires monitoring of multiple cerebral biomarkers simultaneously with high resolution. Photoacoustic microscopy resolves single capillaries, allowing investigations into the most affected types of vessels.
View Article and Find Full Text PDFVirchows Arch
December 2024
Department of Cardiology, Hospital Álvaro Cunqueiro, Vigo, Spain.
Amyloidosis is a rare disease that can affect genitourinary organs but the involvement of the prostate has been documented in a limited number of cases. We have reviewed morphologic and immunohistochemical features of prostate biopsies or surgical specimens in which an initial diagnosis of amyloidosis was made. Prostatic amyloidosis was diagnosed in 25 patients, 21 of them were needle biopsies (1.
View Article and Find Full Text PDFAnn Intern Med
December 2024
The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, and School of Medicine, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel (H.B.F.).
Background: Yellow nail syndrome (YNS) is a rare disorder characterized by a triad of yellow dystrophic nails, lymphedema, and chronic lung disease. Most patients present in adulthood, with only a few congenital or familial cases described. The cause of YNS remains largely unknown, although defects in lymphatic vessel development are suggested to play a significant role.
View Article and Find Full Text PDFObjective: Aim: Using morphometric methods to study the features of endotheliocyte remodeling of the arterial and venous beds of the testicles during long-term ethanol intoxication.
Patients And Methods: Materials and Methods: Endotheliocytes of the arterial and venous bed of the left and right testes of 60 white male rats, which were divided into two groups, were morphologically studied. The 1 group consisted of 30 intact animals, the 2 - 30 rats, which were daily intragastrically injected with a 30 % ethanol solution at the rate of 2 ml per 100 g of the animal's weight for 28 days.
An expert case is presented in which a man was found dead in his apartment, on the bed. Upon examination of the crime scene, the deceased was found to have a contused wound of the frontoparietal region on the left side. The apartment contained a large number of bloodstains, including patterns characteristic of arterial spurt.
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