Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease
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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.
Glossary
- ADSP=
- Alzheimer Disease Sequencing Project;
- CH=
- Caribbean Hispanic;
- HLOD=
- heterogeneity logarithm of the odds;
- LOAD=
- late-onset Alzheimer disease;
- LOD=
- logarithm of the odds;
- LRP1=
- LDL-receptor-related protein 1;
- MAF=
- Minor allele frequency;
- NHGRI=
- National Human Genome Research Institute;
- NHW=
- non-Hispanic white;
- NOS1AP=
- nitric oxide synthase 1 adaptor protein;
- QC=
- quality control;
- SNP=
- single nucleotide polymorphism;
- WES=
- whole exome sequencing;
- WGS=
- whole genome sequencing
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
Co-contributors are listed at links.lww.com/NXG/A132.
The Article Processing Charge was funded by the authors.
- Received February 6, 2018.
- Accepted in final form October 3, 2018.
- Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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