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

Prokopenko, Dmitry, Morgan, Sarah L., Mullin, Kristina, Hofmann, Oliver, Chapman, Brad, Kirchner, Rory, Alzheimer's Disease Neuroimaging Initiative (ADNI), Amberkar, Sandeep +5 more·2021·Alzheimer's & Dementia
DOI 10.1002/alz.12319PMC PMC8519060

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Abstract

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.

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  • Among 149 identified familial AD and GWAS locus genes, 74 genes (49%) were differentially expressed for at least one cell type.

    “We found that 74 genes (49%) were differentially expressed for at least one cell type, and multiple genes showed region-specific expression, including the lipid transporter ABCA7 (enriched in thalamus), the zinc-finger protein ZNF655 (EC) and the complement receptor CR1 (neocortex)56 (Extended Data Fig. 10).”

    From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [58]

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Authors
Prokopenko, D., Morgan, S. L., Mullin, K., Hofmann, O., Chapman, B., Kirchner, R., (ADNI), A. D. N. I., Amberkar, S., Wohlers, I., Lange, C., Hide, W., Bertram, L., & Tanzi, R. E.
Affiliations
  • Genetics and Aging Research Unit and The Henry and Allison McCance Center for Brain Health Department of Neurology Massachusetts General Hospital Boston Massachusetts USA
  • Department of Neuroscience Sheffield Institute for Translational Neurosciences University of Sheffield Sheffield UK
  • Department of Clinical Pathology University of Melbourne Melbourne VIC Australia
  • Bioinformatics Core, Harvard T.H. Chan School of Public Health Boston Massachusetts USA
  • Lübeck Interdisciplinary Platform for Genome Analytics Institutes of Neurogenetics and Cardiogenetics University of Lübeck Lübeck Germany
  • Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA
  • Harvard Medical School Boston Massachusetts USA
ORCID
Prokopenko, Dmitry
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2021-04-02
Volume
17
Issue
9
Pages
1509-1527
ISSN
  • 1552-5260
  • 1552-5279
DOI
10.1002/alz.12319
PMC
PMC8519060
Cited by
107
References
15
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Funders
  • Cure Alzheimer's Fund
  • National Institutes of Health (R01MH060009 (RET), P50AG08702, P30AG028377, P30AG010133, PO1AG05138)

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