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[Preprint]. 2024 Sep 12:2024.09.11.24313439.
doi: 10.1101/2024.09.11.24313439.

Identification of 16 novel Alzheimer's disease susceptibility loci using multi-ancestry meta-analyses of clinical Alzheimer's disease and AD-by-proxy cases from four whole genome sequencing datasets

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

Identification of 16 novel Alzheimer's disease susceptibility loci using multi-ancestry meta-analyses of clinical Alzheimer's disease and AD-by-proxy cases from four whole genome sequencing datasets

Julian Daniel Sunday Willett et al. medRxiv. .

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been previously identified, few studies have analyzed individuals of non-European ancestry. Here, we describe a multi-ancestry genome-wide association study of clinically-diagnosed AD and AD-by-proxy using whole genome sequencing data from NIAGADS, NIMH, 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 are of non-European ancestry. 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) which were also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using WGS-based GWAS of diverse cohorts.

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Figures

Figure 1.
Figure 1.
Study design.
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.
Figure 3.
Figure 3.
Manhattan plots of AD from NIAGADS alone and after meta-analyzing with NIMH. Red genome-wide significant variants represent variants that passed all quality-control testing. NL signifies a new locus.
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.
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