Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.

中文翻译：

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成像衍生表型的听力困难多效性的性别差异：一项全脑调查

听力困难（HD）是老年人的主要健康负担之一。虽然周围听觉系统与衰老相关的变化发挥着重要作用，但与大脑结构和功能相关的遗传变异也可能与 HD 易感性有关。我们分析了一项大规模 HD 全基因组关联研究（GWAS；Ntotal = 501,825，56% 女性），以及与 3,935 个脑成像衍生表型 (IDP) 相关的 GWAS 数据，这些数据对多达 33,224 名个体（52% 女性）进行了评估，使用多个磁共振成像方式。为了研究 HD 多效性与大脑结构和功能的关系，我们进行了遗传相关性、潜在因果变量、孟德尔随机化和多变量广义线性回归分析。此外，我们还进行了局部遗传相关性和多性状共定位分析，以确定与 HD 和大脑 IDP 之间共享的多效性机制有关的基因组区域和基因座。我们观察到 HD 与 120 名女性 IDP、89 名男性 IDP 和 171 名 IDP 性别组合分析中存在广泛的遗传相关性。潜在因果变量分析表明，其中一些遗传相关性可能是由于因果关系。对于七个相关性，因果效应也通过孟德尔随机化方法得到了证实：性别组合分析中的血管体积→HD；女性海马体积→HD、小脑灰质体积→HD、初级视皮层体积→HD、HD→女性静息态功能MRI 100维中第46节点波动幅度；整体平均厚度→HD和HD→男性上辐射冠的平均方向色散指数。当地遗传相关分析确定了 HD 和这 7 个国内流离失所者之间的 13 个多效性区域。我们还观察到女性 HD、初级视觉皮层体积和 SPTBN1 转录组调控之间 rs13026575 变异的共定位信号。大脑结构和功能可能通过可能的因果关系和共同的调节机制在 HD 易感性的性别差异中发挥作用。