Identification of Sex-Specific Genetic Variants Associated With Tau PET

Xin Wang; Iris Broce; Kacie D Deters; Chun Chieh Fan; Sarah Jane Banks

doi:10.1212/NXG.0000000000200043

Identification of Sex-Specific Genetic Variants Associated With Tau PET

Neurol Genet. 2022 Dec 8;8(6):e200043. doi: 10.1212/NXG.0000000000200043. eCollection 2022 Dec.

Authors

Xin Wang¹, Iris Broce¹, Kacie D Deters¹, Chun Chieh Fan¹, Sarah Jane Banks¹

Affiliation

¹ Department of Neurosciences (X.W., I.B., K.D.D., C.C.F., S.J.B.), University of California; and Center for Multimodal Imaging and Genetics (X.W., I.B., C.C.F., S.J.B.), University of California, San Diego, La Jolla.

Abstract

Background and objectives: Important sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET.

Methods: Four hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and ¹⁸F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: BIN1, MS4A6A, DNAJA2, FERMT2, APOC1, APOC1P1, FAM193B, C2orf47, TYW5, and CR1. Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, APOE ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.

Results: We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within DNAJA2, rs113357081 within FERMT2, and rs74614106 within TYW5. In men, we also identified 3 loci within CR1 associated with tau deposits: rs115096248, rs113698814, and rs78150633.

Discussion: Our findings revealed sex-specific genetic variants associated with tau deposition independent of APOE ε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.

Abstract

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