Identification of sex‐specific genetic variants associated with tau‐PET. (20th December 2022)

• Record Type: Journal Article
• Authors: Wang, Xin; Broce‐Diaz, Iris; Deters, Kacie D; Fan, Chun Chieh; Banks, Sarah J.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 6
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.061962
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Abnormal tau deposition is an important pathological feature of AD. Important sex differences exist, with women showing greater tau deposition along the AD continuum compared to men. Our group has previously shown sex differences in the genetic risk associated with AD. However, whether specific genetic variants are associated with sex differences in tau aggregation remains unknown. This study aims to identify sex‐specific genetic variants associated with tau deposition. Method: We included 493 subjects (women n = 246, men n = 247) from the ADNI‐3 study with genotyping data and [ 18 F]Flortaucipir tau PET data. Genetic data underwent standard quality control procedures to remove single nucleotide polymorphisms (SNPs) with more than 5% missingness, failing the Hardy–Weinberg equilibrium test at p = 1 × 10 −6 and minor allele frequency < 1%. Participants were all white and included irrespective of clinical diagnosis (CN, MCI and AD). We focused our analysis on genetic variants within 10 genes previously shown to have sex‐dependent effects in AD to reduce the burden of multiple comparisons: BIN1, MS4A6A, DNAJA2, FERMT2, APOC1, APOC1P1, FAM193B, C2orf47, TYW5, CR1 . One‐way multivariate analysis of variance (MANOVA) was applied to identify genetic variants associated with tau PET data in three ROIs (composite regions of Braak1, Braak34 and Braak56 stages) in women and men separately. We controlled for age, scanner, amyloid status, APOE ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 20 genetic principal components to adjust for population stratification. Bonferroni correction was applied within each gene based on the number of SNPs tested. Result: Table 1 shows the significant genetic variants associated with tau PET. We identified three novel genetic loci associated with tau deposition specifically in women: DNAJA2 rs79711283, FERMT2 rs113357081 and TYW5 rs74614106. In men, three loci within CR1 : rs115096248, rs113698814, rs78150633 were found significantly associated with tau burden. Conclusion: Our findings discovered sex‐specific genetic variants associated with tau deposition independent of APOE ε4, amyloid and clinical diagnosis. These results provide potential gene targets for understanding the mechanism of sex‐specific tau aggregation and developing sex‐specific gene‐guided precision prevention or therapeutic interventions for AD.