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Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262744 | PMC |
http://dx.doi.org/10.1093/hmg/ddae067 | DOI Listing |
Asia Pac J Public Health
December 2024
University Center for Research and Development, Chandigarh University, Mohali, India.
Gestational diabetes mellitus (GDM) is a major global health concern, affecting maternal and child health. Although genetic predispositions and individual medical histories are well-recognized risk factors, emerging research suggests a significant impact of external factors like neighborhood socioeconomic characteristics. This study systematically reviews and meta-analyzes the association between neighborhood deprivation and GDM incidence.
View Article and Find Full Text PDFWorld Allergy Organ J
December 2024
Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.
Background: Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment.
View Article and Find Full Text PDFBrain Spine
November 2024
Neurosurgical Department, "KAT" General Hospital of Athens, Greece.
Introduction: Klippel-Trenaunay Syndrome (KTS) is a rare congenital condition characterized by vascular malformations, bone abnormalities, and limb overgrowth. The genetic basis of KTS is not fully understood, and the diagnosis relies on clinical features. Its clinical spectrum includes several neurosurgical diagnoses, such as cavernous hemangiomas, arteriovenous fistulas, and Chiari I malformation.
View Article and Find Full Text PDFJ Multidiscip Healthc
December 2024
Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, People's Republic of China.
Introduction: Previous observational studies have indicated an association between social isolation and an increased risk of cardiovascular diseases such as angina, but various factors may confound these studies. This study employs Mendelian randomization to investigate the causal relationship between social isolation and angina, minimizing potential confounding effects.
Methods: We conducted a two-sample Mendelian randomization analysis using genetic variants as instrumental variables for social isolation.
Front Immunol
December 2024
State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China.
Background: To determine the role of N-methyladenosine (mA) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).
Methods: Consensus clustering was performed to identify the subgroups with distinct immune or mA modification patterns using profiles from TCGA. A risk score model was constructed using least absolute shrinkage and selection operator regression and validated in two independent cohorts and LUAD tissue microarrays.
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