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Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (, p-value = 5.292 × 10, OR = 0.437, SE = 0.182) in the gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.
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http://dx.doi.org/10.7554/eLife.99200 | DOI Listing |
Mol Genet Genomics
September 2025
Department of Bioscience, Faculdade de Odontologia de Piracicaba, Universidade de Campinas (FOP/UNICAMP), Piracicaba, SP, Brazil.
Variant classification in genetic testing often culminates in "uncertain" calls, known as variants of uncertain significance (VUS), which remain a major clinical challenge. Among the established criteria for variant classification, population allele frequency (AF) is fundamental, yet under-representation of non-European groups hinders accurate interpretation. In this study, we evaluated the impact of population-specific AF on the reclassification of VUS and conflicting variants in hereditary cancer genes.
View Article and Find Full Text PDFJ Crohns Colitis
July 2025
Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Background And Aims: Monogenic forms of inflammatory bowel disease (IBD) are driven by variants in genes critical to pathways in intestinal homeostasis and immunity. We investigated gene- and variant-level effects of these genes with IBD and phenome-wide association, leveraging large-scale whole exome sequencing data across 4 diverse cohorts: BioMe Biobank (Regeneron and Sema4), Penn Med Biobank, and UK Biobank.
Methods: Predicted loss- and gain-of function variants were extracted from 102 monogenic genes.
medRxiv
July 2025
Genomic Medicine Institute, Cleveland Clinic Research, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, United States of America.
Background: The Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD) is a multicenter collaboration aimed at understanding the genetic architecture of Parkinson's disease (PD) in this underrepresented population using data from 15 countries across the Americas and the Caribbean. In this study, we conducted the largest genome-wide association studies (GWAS) for PD susceptibility in Latin Americans.
Methods: We analyzed genotype data from LARGE-PD Phase 1 (n = 1,498) and Phase 2 (n = 4,401) using multiple GWAS approaches: SAIGE, which incorporates a genetic relationship matrix in the model; ATT, which includes global ancestry on the model; TRACTOR, which splits allele dosages by ancestry to detect ancestry-specific risk loci; and admixture mapping.
medRxiv
August 2025
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Genome-wide association studies (GWAS) have been successful in identifying over 100 loci associated with Parkinson's disease (PD) susceptibility. However, the majority of these studies have focused on European cohorts with few including diverse ancestries. Using genotyped and imputed data from 691 South African PD cases and 826 controls, we conducted a conventional GWAS, two local ancestry GWAS (LA-GWAS) approaches (one using local ancestry as a covariate and the other separating the dosage per ancestry), and an association analysis to identify regions of homozygosity associated with PD status.
View Article and Find Full Text PDFClin Genet
August 2025
Postgraduate Program in Internal Medicine, Federal University of Paraná (UFPR), Curitiba, Brazil.
The Mennonite population has a unique history of 500 years of genetic isolation shaped by at least three demographic bottlenecks, founder effects, inbreeding, epidemics, and migrations. To evaluate their susceptibility for monogenic diseases (MD), we performed whole-exome sequencing on 325 volunteers from two South Brazilian Mennonite settlements (one urban and another rural). We identified 23 pathogenic variants (P) and 27 likely P, with 22.
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