Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
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Published:2023-04-26
Issue:1
Volume:11
Page:
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ISSN:2051-5960
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Container-title:Acta Neuropathologica Communications
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language:en
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Short-container-title:acta neuropathol commun
Author:
Ali Muhammad, Archer Derek B., Gorijala Priyanka, Western Daniel, Timsina Jigyasha, Fernández Maria V., Wang Ting-Chen, Satizabal Claudia L., Yang Qiong, Beiser Alexa S., Wang Ruiqi, Chen Gengsheng, Gordon Brian, Benzinger Tammie L. S., Xiong Chengjie, Morris John C., Bateman Randall J., Karch Celeste M., McDade Eric, Goate Alison, Seshadri Sudha, Mayeux Richard P., Sperling Reisa A., Buckley Rachel F., Johnson Keith A., Won Hong-Hee, Jung Sang-Hyuk, Kim Hang-Rai, Seo Sang Won, Kim Hee Jin, Mormino Elizabeth, Laws Simon M., Fan Kang-Hsien, Kamboh M. Ilyas, Vemuri Prashanthi, Ramanan Vijay K., Yang Hyun-Sik, Wenzel Allen, Rajula Hema Sekhar Reddy, Mishra Aniket, Dufouil Carole, Debette Stephanie, Lopez Oscar L., DeKosky Steven T., Tao Feifei, Nagle Michael W., Hohman Timothy J., Sung Yun Ju, Dumitrescu Logan, Cruchaga CarlosORCID, , , , ,
Abstract
AbstractAmyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) 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 ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 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; β = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 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, β = 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, β = 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.
Funder
National Institutes of Health Michael J. Fox Foundation for Parkinson's Research
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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