Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

Brian W. Kunkle, James Jaworski, Sandra Barral, Badri Vardarajan, Gary W. Beecham, Eden R. Martin, Laura S. Cantwell, Amanda Partch, Thomas D. Bird, Wendy H. Raskind, Anita L. Destefano, Regina M. Carney, Michael Cuccaro, Jeffrey M. Vance, Lindsay A. Farrer, Alison M. Goate, Tatiana Foroud, Richard P. Mayeux, Gerard D. Schellenberg, Jonathan L. HainesMargaret A. Pericak-Vance

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2-10
Number of pages9
JournalAlzheimer's and Dementia
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Familial
  • Genetics
  • High penetrance
  • Identity by descent
  • Late-onset Alzheimer's disease
  • Linkage
  • Non-Hispanic white

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease'. Together they form a unique fingerprint.

  • Cite this

    Kunkle, B. W., Jaworski, J., Barral, S., Vardarajan, B., Beecham, G. W., Martin, E. R., Cantwell, L. S., Partch, A., Bird, T. D., Raskind, W. H., Destefano, A. L., Carney, R. M., Cuccaro, M., Vance, J. M., Farrer, L. A., Goate, A. M., Foroud, T., Mayeux, R. P., Schellenberg, G. D., ... Pericak-Vance, M. A. (2016). Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease. Alzheimer's and Dementia, 12(1), 2-10. https://doi.org/10.1016/j.jalz.2015.05.020