Whole‐genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development

Introduction Genome‐wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole‐genome sequencing (WGS) now permits genome‐wide analyses to identify rare variants contributing to AD risk. Methods We performed single‐variant and spatial clustering–b...

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Published inAlzheimer's & dementia Vol. 17; no. 9; pp. 1509 - 1527
Main Authors Prokopenko, Dmitry, Morgan, Sarah L., Mullin, Kristina, Hofmann, Oliver, Chapman, Brad, Kirchner, Rory, Amberkar, Sandeep, Wohlers, Inken, Lange, Christoph, Hide, Winston, Bertram, Lars, Tanzi, Rudolph E.
Format Journal Article
LanguageEnglish
Published United States John Wiley and Sons Inc 01.09.2021
Subjects
Alzheimer Disease - genetics
Alzheimer's disease
family‐based association study
Gene Frequency - genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Ion Channels - genetics
Kinesins - genetics
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Membrane Proteins - genetics
Microtubule-Associated Proteins - genetics
neuronal development
Proteins - genetics
rare variants
RVAS
synaptic function
Whole Genome Sequencing
RVAS
neuronal development
rare variants
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synaptic function
whole-genome sequencing
family-based association study
Alzheimer's disease
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ISSN1552-5260
1552-5279
1552-5279
DOI10.1002/alz.12319

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Summary:Introduction Genome‐wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole‐genome sequencing (WGS) now permits genome‐wide analyses to identify rare variants contributing to AD risk. Methods We performed single‐variant and spatial clustering–based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family‐based WGS‐based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. Results We identified 13 new AD candidate loci that yielded consistent rare‐variant signals in discovery and replication cohorts (4 from single‐variant, 9 from spatial‐clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. Discussion Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD‐associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD‐associated rare variants, particularly outside of the exome.
Bibliography:Dmitry Prokopenko and Sarah L. Morgan contributed equally.
http://adni.loni.usc.edu/wp‐content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Alzheimer's Disease Neuroimaging Initiative (ADNI): Data used in preparation of this article were in part obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at
Christoph Lange, Winston Hide, Lars Bertram, and Rudolph E. Tanzi jointly supervised this work.
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Alzheimer's Disease Neuroimaging Initiative (ADNI): Data used in preparation of this article were in part obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp‐content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.12319