Document Type
Journal Article
Publication Title
Acta Neuropathologica Communications
Volume
11
Issue
1
PubMed ID
37101235
Publisher
Springer
School
Centre for Precision Health
RAS ID
55078
Funders
National Institutes of Health
Abstract
Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (AB) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE 4; rs429358; = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE 4, and five additional novel associations (APOE 2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE 4. APOE 4 and 2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.
DOI
10.1186/s40478-023-01563-4
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Ali, M., Archer, D. B., Gorijala, P., Western, D., Timsina, J., Fernández, M. V., ... & Cruchaga, C. (2023). Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease. Acta neuropathologica communications, 11(1), article 68. https://doi.org/10.1186/s40478-023-01563-4