Background: Identification of rare variants involved in complex, polygenic diseases like Crohn's disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated outside the discovery population. Prior studies implied that the three known rare variants in NOD2 are absent in West African and Asian populations and only contribute in African Americans via admixture.
Methods: Whole genome sequencing (WGS) data from 3418 African American individuals, 1774 inflammatory bowel disease (IBD) cases, and 1644 controls were used to assess odds ratios and allele frequencies (AF), as well as haplotype-specific ancestral origins of European-derived CD variants discovered in a large exome-wide association study. Local and global ancestry was performed to assess the contribution of admixture to IBD contrasting European and African American cohorts.
Results: Twenty-five rare variants associated with CD in European discovery cohorts are typically five-fold lower frequency in African Americans. Correspondingly, where comparisons could be made, the rare variants were found to have a predicted four-fold reduced burden for IBD in African Americans, when compared to European individuals. Almost all of the rare CD European variants were found on European haplotypes in the African American cohort, implying that they contribute to disease risk in African Americans primarily due to recent admixture. In addition, proportion of European ancestry correlates the number of rare CD European variants each African American individual carry, as well as their polygenic risk of disease. Similar findings were observed for 23 mutations affecting 10 other common complex diseases for which the rare variants were discovered in European cohorts.
Conclusions: European-derived Crohn's disease rare variants are even more rare in African Americans and contribute to disease risk mainly due to admixture, which needs to be accounted for when performing cross-ancestry genetic assessments.
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http://dx.doi.org/10.1186/s13073-023-01244-w | DOI Listing |
Anat Sci Int
December 2024
Department of Anatomy, School of Medicine, Faculty of Health Sciences, National and Kapodistrian University of Athens, 75 Mikras Asias Str., Goudi, 11527, Athens, Greece.
The cerebral arterial circle morphologic variability has been extensively studied. The posterior cerebral artery (PCA) variants are rarely identified, except from the first segment (P1) hypoplasia or absence. Due to its unique morphology, the computed tomography angiography (CTA) of a 34-year-old female patient was further investigated.
View Article and Find Full Text PDFJ Bone Miner Res
December 2024
Paris Cité University, Reference center for skeletal dysplasia, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital (AP-HP), Paris, France.
Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.
View Article and Find Full Text PDFJ Clin Res Pediatr Endocrinol
December 2024
Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Türkiye.
Objective: Resistance to thyroid hormone beta (RTHβ) is a rare disorder characterized by a fairly heterogeneous clinical presentation due to varying degrees of tissue response to thyroid hormone. The study aimed to evaluate the clinical, laboratory features and genotype-phenotype relationship of Turkish patients with RTHβ.
Methods: Patients who underwent a THRB gene analysis between September 2019 and September 2023 were retrospectively reviewed.
Alzheimers Dement
December 2024
Department of Neurology, Zhongshan Hospital and Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
Introduction: Increasing evidence has highlighted rare variants in Alzheimer's disease (AD). However, insufficient sample sizes, especially in underrepresented ethnic groups, hinder their investigation. Additionally, their impact on endophenotypes remains largely unexplored.
View Article and Find Full Text PDFAm J Med Genet A
December 2024
Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.
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