Sex-aware Cross-tissue Regulatory Transformer Identified Sexually Dimorphic Alzheimer's Disease Risk Loci and Causal Cellular Circuit
· 2026-09-09 · 原文
DOI：10.64898/2026.09.08.26362488v1?rss=1
Sex differences in Alzheimer's disease (AD) genetic effects and regulatory contexts remain incompletely resolved. We analyzed 449,335 European-ancestry participants using sex-stratified and genotype-by-sex models and developed STAGE-AD, a Transformer integrating molecular QTLs, epigenomic and single-cell annotations. Sex-stratified analyses identified eight female and three male genome-wide-significant signals provisionally classified as novel. Primary test-set area under the precision-recall curve was 0.895 (95% confidence interval, 0.877-0.912), decreasing to 0.751 under locus hold-out and 0.681 under APOE-region hold-out. Statistical-genetic integration in independent HUNT and MVP cohorts supported 236 genes at 106 loci. Prespecified lifetime-risk assumptions yielded liability-scale SNP
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1. 人话版
Sex differences in Alzheimer's disease (AD) genetic effects and regulatory contexts remain incompletely resolved.
We analyzed 449,335 European-ancestry participants using sex-stratified and genotype-by-sex models and developed STAGE-AD, a Transformer integrating molecular QTLs, epigenomic and single-cell annotations.
2. 领域脉络
Sex-stratified analyses identified eight female and three male genome-wide-significant signals provisionally classified as novel.
3. 机制拆解
摘要未展开方法细节——精读时重点看方法/模型部分。
4. 证据与数字
Primary test-set area under the precision-recall curve was 0.895 (95% confidence interval, 0.877-0.912), decreasing to 0.751 under locus hold-out and 0.681 under APOE-region hold-out.
Statistical-genetic integration in independent HUNT and MVP cohorts supported 236 genes at 106 loci.
5. 反例与边界
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6. 跨领域连接与意外收获
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7. 可复用方法
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8. 术语表
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