Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65–3.56, p-value = 7.0 × 10⁻⁶) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10⁻⁴). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer’s-related risk for females with LBD.

性别影响路易体痴呆 (LBD) 的患病率和症状。然而，全基因组关联研究通常关注常染色体变异并排除特定性别的危险因素。我们通过使用来自 2591 个 LBD 病例和 4391 个对照的全基因组序列数据进行 X 染色体范围关联研究来解决这一差距。我们在接受APOE ε4剂量调节的女性 LBD 病例中发现了MAP3K15内含子 1 内的显着风险位点（rs141773145，比值比 = 2.42，95% 置信区间 = 1.65–3.56，p值 = 7.0 × 10 ^-6 ） 。该基因座包含一个增强子区域，可调节源自原代培养神经球的神经节隆起细胞中MAP3K15 的表达。罕见变异负荷测试显示，女性 LBD 病例中TEX13A错义突变存在差异富集，但未达到显着性（p值 = 1.34 × 10 ^-4）。这些发现支持遗传因素的性别特异性影响以及阿尔茨海默氏症相关风险对患有小黑发的女性的潜在作用。