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Meta-Analysis
. 2025 Feb;21(2):e14592.
doi: 10.1002/alz.14592.

Identification of 16 novel Alzheimer's disease loci using multi-ancestry meta-analyses

Julian Daniel Sunday Willett  1 , Mohammad Waqas  1 , Younjung Choi  1 , Tiffany Ngai  1   2 , Kristina Mullin  1 , Rudolph E Tanzi  1 , Dmitry Prokopenko  1
Affiliations
Meta-Analysis

Identification of 16 novel Alzheimer's disease loci using multi-ancestry meta-analyses

Julian Daniel Sunday Willett et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry.

Methods: We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry.

Results: For clinically diagnosed AD, we identified 14 new loci-five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS.

Discussion: In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing-based GWAS of diverse cohorts.

Highlights: We used whole-genome sequencing data from large and diverse cohorts. We found novel genome-wide association study findings based on whole-genome data. We performed a multiancestry meta-analysis and incorporated results from underrepresented groups.

Keywords: All of Us; Alzheimer's disease; Alzheimer's disease by proxy; National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; UK Biobank; genome‐wide association study; population genetics.

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Conflict of interest statement

All authors declare that they have no potential conflicts of interest related to this work. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Study design. AD, Alzheimer's disease; AoU, All of Us; FAVOR, Functional Annotation of Variants Online Resource; HWE, Hardy–Weinberg equilibrium; NIAGADS, National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; NIMH, National Institute of Mental Health; QC, quality control; UKB, UK Biobank; WGS, whole genome sequencing.
FIGURE 2
FIGURE 2
Age (A) and sex (B) demographics of individuals representing AD cases compared to controls in each cohort. NIAGADS used clinical AD as a case definition, with UKB and AoU using AD‐by‐proxy as case definitions. AD, Alzheimer's disease; AoU, All of Us; NIAGADS, National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; UKB, UK Biobank.
FIGURE 3
FIGURE 3
Manhattan plots of AD from NIAGADS alone (A) and after meta‐analyzing with NIMH (B). Red genome‐wide significant variants represent variants that passed all quality‐control testing. NL signifies a new locus. AD, Alzheimer's disease; GWAS, genome‐wide association study; NIAGADS, The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; NIMH, National Institute of Mental Health.
FIGURE 4
FIGURE 4
Manhattan plot of AD‐by‐proxy meta‐analysis, highlighting variants that were nominally significant (P ≤ 0.05) in the NIAGADS–NIMH meta‐analysis. Given the larger number of independent loci proximal to APOE, only one locus in this region was shown. NL signifies a new locus. AD, Alzheimer's disease; AoU, All of Us; APOE, apolipoprotein E; NIAGADS, The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site; NIMH, National Institute of Mental Health; UKB, UK Biobank.
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References

    1. Gustavsson A, Norton N, Fast T, et al. Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimers Dement. 2023;19(2):658‐670. doi:10.1002/alz.12694 - DOI - PubMed
    1. Li X, Feng X, Sun X, Hou N, Han F, Liu Y. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990‐2019. Front Aging Neurosci. 2022;14:937486. doi:10.3389/fnagi.2022.937486 - DOI - PMC - PubMed
    1. Andrews SJ, Renton AE, Fulton‐Howard B, Podlesny‐Drabiniok A, Marcora E, Goate AM. The complex genetic architecture of Alzheimer's disease: novel insights and future directions. EBioMedicine. 2023;90:104511. doi:10.1016/j.ebiom.2023.104511 - 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. 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

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