Sex differences in genetic predictors of resilience to Alzheimer’s disease
Authors: Dumitrescu Logan , Mahoney Emily R. , Mukherjee Shubhabrata , Lee Michael L. , Bush William S. , Engelman Corinne D. , Lu Qiongshi , Fardo David W. , Trittschuh Emily H. , Mez Jesse , Kaczorowski Catherine C. , Widaman Keith F. , Buckley Rachel F. , Properzi Michael J. , Mormino Elizabeth C. , Yang Hyun‐Sik , Andrews Shea J. , Sanders R. Elizabeth , Raghavan Neha S. , Vardarajan Badri N. , Schellenberg Gerard D. , Cruchaga Carlos , Haines Jonathan L. , Keene C. Dirk , Saykin Andrew J. , Larson Eric B. , Sperling Reisa A. , Mayeux Richard , Bennett David A. , Schneider Julie A. , Crane Paul K. , Jefferson Angela L. , Hohman Timothy J. ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team
Published: December 2020

Background

Identifying genetic factors that provide resilience against the clinical consequences of Alzheimer’s disease (AD) pathology is likely to accelerate the development of novel therapeutics. Sex differences in AD prevalence, neuropathological presentation, and clinical progression suggest that exploring the sex‐specific genetic architecture of resilience to AD may be a critical first step towards the characterization and development of precision interventions.

Method

We completed sex‐stratified and sex‐interaction genome‐wide association studies (GWAS) of resilience across 5,109 non‐Hispanic white individuals from two autopsy cohorts (ACT and ROS/MAP) and two positron emission tomography (PET) cohorts (ADNI and A4). A continuous measure of resilience was quantified using latent variable modeling and represented better‐than‐expected cognition for the given level of amyloid in the brain. The final dataset included 2,130 males (77 ± 9 years) and 2,979 females (77 ± 10 years), the majority of whom were cognitively normal (73% of males; 76% of females). GWAS of resilience were performed in the combined autopsy dataset and combined PET dataset individually and then meta‐analyzed. Covariates included age and three principal components. Analyses were run in all individuals as well as in the subset of cognitively normal individuals.

Result

An intergenic variant on chromosome 10 (rs827389, MAF = 0.46) showed a female‐specific genome‐wide significant association with resilience in cognitively normal females (β = 0.08, p = 7.6 × 10−9) but not in males (β = ‐5.3 × 10‐3, p = 0.77; sex interaction p = 1.4 × 10−4). This variant is a modest brain eQTL for the KIN gene that is implicated in DNA repair. We also observed a strong sex‐interaction effect among all individuals on chromosome 3 (rs113968105, MAF = 0.10, p = 7.5 × 10−8), in which the minor allele was associated with higher resilience in males (β = 0.10, p = 4.2 × 10−7) but lower resilience in females (β = ‐0.04, p = 0.03). This variant is an eQTL for three genes, including the acetylcholinesterase binding gene COLQ.

Conclusion

We identified two putative sex‐specific loci that provide protection against the downstream consequences of amyloid pathology. The associations implicate DNA damage repair genes among females, and acetylcholinesterase genes in males, suggesting the pathways providing neuroprotection may differ by sex.