Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

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, Carlos

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

Dokumentdetails

ID

oai:HAL:hal-04228529v1

Thema

Humans Female Alzheimer Disease Amyloid beta-Peptides Genome-Wide Association Study Amyloidosis Amyloid Apolipoproteins E [SDV.SPEE]Life Sciences [q-bio]/Sa...

Autor

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, Carlos

Langue

Editor

HAL CCSD;BioMed Central part of Springer Science

Kategorie

Wissenschaften: Lebenswissenschaften

Jahr

2023

Auflistungsdatum

08.12.2023

Schlüsselwörter

amyloidosis p = 1 disease alzheimer genome-wide study 32 imaging apoe amyloid ɛ4 se = 0 maf = 0 β = 0

Metrisch

Zusammenfassung

International audience; 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, 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, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10, 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, MAF = 0.006, sex-interaction P = 9.8 × 10) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10, MAF = 0.004, sex-interaction P = 1.3 × 10).

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.

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, Carlos, 2023, Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease., HAL CCSD;BioMed Central part of Springer Science