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. 2024 May;20(5):3290-3304.
doi: 10.1002/alz.13705. Epub 2024 Mar 21.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Yanbing Wang  1 , Chloé Sarnowski  1   2 , Honghuang Lin  3 , Achilleas N Pitsillides  1 , Nancy L Heard-Costa  1   4 , Seung Hoan Choi  1 , Dongyu Wang  1 , Joshua C Bis  5 , Elizabeth E Blue  6   7 ; Alzheimer's Disease Neuroimaging Initiative (ADNI); Eric Boerwinkle  2 , Philip L De Jager  8   9 , Myriam Fornage  2   10 , Ellen M Wijsman  11 , Sudha Seshadri  4   12   13 , Josée Dupuis  1   14 , Gina M Peloso  1 , Anita L DeStefano  1   4 ; Alzheimer's Disease Sequencing Project (ADSP)
Affiliations

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Yanbing Wang et al. Alzheimers Dement. 2024 May.

Abstract

Introduction: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci.

Methods: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants.

Results: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses.

Discussion: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Keywords: Alzheimer's disease; association analyses; diverse populations; genome‐wide association study; single nucleotide variations; whole genome sequencing.

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Conflict of interest statement

The authors do not have declarations of interest to report. The funding sources of this study had no role in the study design, the collection, the analysis or the interpretation of data, in the writing of the report, or in the decision to submit the article for publication. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Schematic of the ADSP 5K analysis. ADNI, Alzheimer's Disease Neuroimaging Initiative; ADSP, Alzheimer's Disease Sequencing Project; GWAS, genome‐wide association studies; WGS, whole genome sequence.
FIGURE 2
FIGURE 2
Top variants identified from single‐variant association analysis in the pooled ADSP sample within 100 kb of the 83 lead genome‐wide association studies (GWAS) variants. Variant ID is in the form of chromosome:position (effect allele). The positions provided are on build 38. EAF is the effect allele frequency, Meta‐RE is the multi‐population meta‐analysis using a random effect model, Meta‐FE is the multi‐population meta‐analysis using a fixed effect model. The p‐value for Meta‐RE is calculated using Han and Eskin's modified random effects model. The effect size and its 95% CI are not shown for variants with a minor allele count (MAC) < 10 in population‐specific analysis. AA, Black/African‐American; EA, White/European ancestry; HI, Hispanic/Latino.
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References

    1. Karlsson IK, Escott‐Price V, Gatz M, et al. Measuring heritable contributions to alzheimer's disease: polygenic risk score analysis with twins. Brain Commun. 2022;4(1):fcab308. doi:10.1093/braincomms/fcab308 - DOI - PMC - PubMed
    1. Beecham GW, Bis JC, Martin ER, et al. The alzheimer's disease sequencing project: study design and sample selection. Neurol Genet. 2017;3(5):e194. doi:10.1212/NXG.0000000000000194 - DOI - PMC - PubMed
    1. Bellenguez C, Kucukali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54(4):412‐436. doi:10.1038/s41588-022-01024-z - DOI - PMC - PubMed
    1. Prokopenko D, Morgan SL, Mullin K, et al. Whole‐genome sequencing reveals new Alzheimer's disease‐associated rare variants in loci related to synaptic function and neuronal development. Alzheimers Dement. 2021;17(9):1509‐1527. doi:10.1002/alz.12319 - DOI - PMC - PubMed
    1. Prokopenko D, Lee S, Hecker J, et al. Region‐based analysis of rare genomic variants in whole‐genome sequencing datasets reveal two novel Alzheimer's disease‐associated genes: DTNB and DLG2. Mol Psychiatry. 2022;27(4):1963‐1969. doi:10.1038/s41380-022-01475-0 - DOI - PMC - PubMed