Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
Muhammad Ali, Derek B. Archer, Priyanka Gorijala, Daniel Western, Jigyasha Timsina, María Victoria Fernández, Ting‐Chen Wang, Claudia L. Satizábal, Qiong Yang, Alexa Beiser, Ruiqi Wang, Gengsheng Chen, Brian A. Gordon, Tammie L.S. Benzinger, Chengjie Xiong, John C. Morris, Randall J. Bateman, Celeste M. Karch, Eric McDade, Alison Goate, Sudha Seshadri, Richard Mayeux, Reisa A. Sperling, Rachel F. Buckley, Keith A. Johnson, Hong‐Hee Won, Sang‐Hyuk Jung, Hang‐Rai Kim, Sang Won Seo, Hee Jin Kim, Elizabeth C. Mormino, Simon M. Laws, Kang-Hsien Fan, M. Ilyas Kamboh, Prashanthi Vemuri, Vijay K. Ramanan, Hyun‐Sik Yang, Allen Wenzel, Hema Sekhar Reddy Rajula, Aniket Mishra, Carole Dufouil, Stéphanie Debette, Oscar L. López, Steven T. DeKosky, Feifei Tao, Michael W. Nagle, the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, the Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Timothy J. Hohman, Yun Ju Sung, Logan Dumitrescu, Carlos Cruchaga
Abstract
Abstract Amyloid 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.