Sex‐specific genetic architecture of late‐life memory performance

Eissman, Jaclyn M.; Archer, Derek B.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo‐Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse B.; Bush, William S.; Kunkle, Brian W.; Naj, Adam C.; Gifford, Katherine A.; ,; Cuccaro, Michael L.; Cruchaga, Carlos; Pericak‐Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li‐San; Schellenberg, Gerard D.; Mayeux, Richard P.; Haines, Jonathan L.; Jefferson, Angela L.; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Thompson, Paul M.; Martin, Eden R.; Bennett, David A.; Barnes, Lisa L.; Schneider, Julie A.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan

doi:10.1002/alz.13507

Cited by 1 publication

(1 citation statement)

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“…Our findings from the sex-specific GWAS identified significantly associated SNPs on chromosome 2q (BIN1 locus) and 4q (QRFPR) for case-control ncAD in females only providing new insights into the gender-specific genetic basis for AD progression. In a recent sex-specific clinical GWAS for AD, BIN1 was also identified as having a female-specific association 28 . Another investigation, estimating hazard ratios, revealed that BIN1 contributes to a higher risk in females compared to males 29 .…”

Section: Discussionmentioning

confidence: 99%

Neuropathology-based GWAS for Alzheimer’s disease reveals novel susceptibility loci and highlights sex-specific pathways

Jin,

Topaloudi,

Shekhar

et al. 2023

Preprint

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Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer’s disease (AD) being the most common type. While Genome-wide Association Studies (GWAS) of clinically defined AD have identified multiple AD susceptibility variants, a significant portion of the heritability remains unexplained highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women’s increased susceptibility to dementia there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features which are the gold standard for diagnosis and pursuing sex-specific analysis. We bring together 13 different genomic and neuropathology datasets (6,960 individuals) and we integrate our GWAS findings with transcriptomic and proteomic data (ROSMAP and Mayo studies) aiming to also identify in vivo biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1, OPCML, and CDH4. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Tissue-specific associations in females, particularly in the ovary issue, suggest a connection between sex hormones and AD. Finally, we pursue the identification of in-vivo biomarkers associated with AD neuropathology, with a goal to offer insights into disease progression and potential therapeutic targets. Our findings contribute to unraveling the molecular basis of AD, emphasizing the importance of sex-specific analyses and multi-omics approaches. Further research is needed to validate and explore the clinical utility of these findings.

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Section: Discussionmentioning

confidence: 99%