Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease

Gary W. Beecham, Badri Vardarajan, Elizabeth Blue, William Bush, James Jaworski, Sandra Barral, Anita De Stefano, Kara Hamilton-Nelson, Brian Kunkle, Eden R. Martin, Adam Naj, Margaret A. Pericak-Vance, Christian Reitz, Timothy Thornton, Cornelia van Duijn, Allison Goate, Sudha Seshadri, Lindsay A. Farrer, Eric Boerwinkle, Gerard SchellenbergJonathan L. Haines, Ellen Wijsman, Richard Mayeux, Margaret A. Pericak-Vance

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Objective To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). Methods As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test. Results We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates. Conclusions We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.

Original languageEnglish (US)
Article numbere286
JournalNeurology: Genetics
Volume4
Issue number6
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease'. Together they form a unique fingerprint.

  • Cite this

    Beecham, G. W., Vardarajan, B., Blue, E., Bush, W., Jaworski, J., Barral, S., Stefano, A. D., Hamilton-Nelson, K., Kunkle, B., Martin, E. R., Naj, A., Pericak-Vance, M. A., Reitz, C., Thornton, T., Duijn, C. V., Goate, A., Seshadri, S., Farrer, L. A., Boerwinkle, E., ... Pericak-Vance, M. A. (2018). Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease. Neurology: Genetics, 4(6), [e286]. https://doi.org/10.1212/NXG.0000000000000286