| Title: |
Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease |
| Authors: |
Eissman, JM; Dumitrescu, L; Mahoney, ER; Smith, AN; Mukherjee, S; Lee, ML; Scollard, P; Choi, SE; Bush, WS; Engelman, CD; Lu, Q; Fardo, DW; Trittschuh, EH; Mez, J; Kaczorowski, CC; Hernandez Saucedo, H; Widaman, KF; Buckley, RF; Properzi, MJ; Mormino, EC; Yang, HS; Harrison, TM; Hedden, T; Nho, K; Andrews, SJ; Tommet, D; Hadad, N; Sanders, RE; Ruderfer, DM; Gifford, KA; Zhong, X; Raghavan, NS; Vardarajan, BN; Pericak-Vance, MA; Farrer, LA; Wang, LS; Cruchaga, C; Schellenberg, GD; Cox, NJ; Haines, JL; Keene, CD; Saykin, AJ; Larson, EB; Sperling, RA; Mayeux, R; Cuccaro, ML; Bennett, DA; Schneider, JA; Crane, PK; Jefferson, AL; Hohman, TJ |
| Publisher Information: |
OXFORD UNIV PRESS |
| Publication Year: |
2022 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0006-8950 |
| Relation: |
pii: 6585174; https://hdl.handle.net/11343/307671 |
| Availability: |
https://hdl.handle.net/11343/307671 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0 ; CC BY-NC |
| Accession Number: |
edsbas.42036B6 |
| Database: |
BASE |