Journal
ALZHEIMERS & DEMENTIA
Volume 12, Issue 1, Pages 2-10Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2015.05.020
Keywords
Non-Hispanic white; Late-onset Alzheimer's disease; Linkage; High penetrance; Identity by descent; Familial; Genetics
Categories
Funding
- National Institute of Health [R01 AG027944, R01 AG019085, R01 AG028786-02, RC2AG036528, R37AG015473, U01AG032934, R01-AG025259, P30-AG13846, 1R01 NS069719-01]
- Alzheimer Disease Research Center Genetics Core grant [5P50-AG008702-25]
- VA Medical Research Funds
- Alzheimer's Association grant [IIRG09133827]
- Department of Veterans Affairs Merit Review Award
- VA Puget Sound Health Care System Geriatric Research, Education, and Clinical Center
- French National Foundation on Alzheimer's disease and related disorders
- Labex (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]
- NIA [AG081220]
- AGES [N01-AG-12100]
- NIMBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center and Erasmus University
- Alzheimer's Association [ADGC-10-196728]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001108] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL105756] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS069719] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [U24AG056270, U01AG032984, U24AG021886, R37AG015473, P50AG008702, R01AG025259, R01AG027944, RC2AG036528, UF1AG047133, P30AG013846, R01AG028786, R01AG019085, R01AG041797] Funding Source: NIH RePORTER
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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 epsilon 4 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. (C) 2016 The Authors. Published by Elsevier Inc.
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