AU - Nassan, Malik AU - Piras, Ignazio s AU - Rogalski, Emily AU - Geula, Changiz AU - Mesulam, M-Marsel AU - Huentelman, Matt TI -评估遗传代理神经发育语言表型与原发性进步性失语症风险之间的关联- 10.1212/WNL.0000000000207136DP - 2023三月08 TA -神经病学半岛投注体育官网PG - 10.1212/WNL。0000000000207136 4099 - http://n.半岛投注体育官网neurology.org/content/early/2023/03/08/WNL.0000000000207136.short 4100 - //www.ebmtp.com/content/early/2023/03/08/WNL.0000000000207136.full AB -背景和目的:原发性进行性失语症(PPA)是一种进行性语言能力下降的神经退行性综合征。PPA有3个主要的子类型:语义型、语义型和语法型。观察性研究表明，语言相关的神经发育表型与PPA风险增加之间存在关联。我们试图通过孟德尔随机化(MR)方法评估这种关系，该方法可以提示潜在的因果关系。方法:与阅读障碍(42个SNPs)、发育性语言障碍(29个SNPs)和左撇子(41个SNPs)相关的全基因组显著单核苷酸多态性(SNPs)被用作暴露的遗传代理。18/41左撇子snp与大脑皮层结构不对称有关。GWAS汇总统计数据来自公开的语义数据库(308例/ 616个对照)和语法PPA数据库(269例/ 538个对照)。无logopenic PPA(324例/ 3444例对照组)通过“临床诊断为伴有显著语言障碍的阿尔茨海默病”的标题进行代理近似。 Inverse weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results.Results: Dyslexia, developmental speech disorders and left-handedness were not associated with any PPA subtype (P > 0.05). The genetic proxy of cortical asymmetry in left handedness was significantly associated with agrammatic PPA (beta = 4.3, P= 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses.Discussion: Our results do not support a causal association between dyslexia, developmental speech disorders, or handedness with any of the PPA subtypes. Our data suggests a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left handedness is necessary remains to be determined but is unlikely given the absence of association between left handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.