Browsing by Subject "Familial"

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    Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease
    (Elsevier, 2016-01) Kunkle, Brian W.; Jaworski, James; Barral, Sandra; Vardarajan, Badri; Beecham, Gary W.; Martin, Eden R.; Cantwell, Laura S.; Partch, Amanda; Bird, Thomas D.; Raskind, Wendy H.; DeStefano, Anita L.; Carney, Regina M.; Cuccaro, Michael; Vance, Jeffrey M.; Farrer, Lindsay A.; Goate, Alison M.; Foroud, Tatiana; Mayeux, Richard P.; Schellenberg, Gerard D.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Department of Medical and Molecular Genetics, IU School of Medicine
    INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
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    New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis
    (American Heart Association, 2022) Aldred, Micheala A.; Morrell, Nicholas W.; Guignabert, Christophe; Medicine, School of Medicine
    Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with poor prognosis characterized by functional and structural alterations of the pulmonary circulation causing marked increase in pulmonary vascular resistance (PVR), ultimately leading to right heart failure and death. Mutations in the gene encoding Bone Morphogenetic Protein Receptor type 2 (BMPR2), a receptor for the transforming growth factor-beta (TGF-β) superfamily, account for over 70% of families with PAH, and approximately 20% of sporadic cases. In recent years, however, less common or rare mutations in other genes have been identified. This review will consider how these newly discovered PAH genes could help to provide a better understanding of the molecular and cellular bases of the maintenance of the pulmonary vascular integrity, as well as their role in the PAH pathogenesis underlying occlusion of arterioles in the lung. We will also discuss how insights into the genetic contributions of these new PAH-related genes may open up new therapeutic targets for this, currently incurable, cardiopulmonary disorder.