听力困难与影像学衍生表型的多效性中的性别差异：全脑研究。

Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation.

作者信息

He Jun, Cabrera-Mendoza Brenda, Angelis Flavio De, Pathak Gita A, Koller Dora, Curhan Sharon G, Curhan Gary C, Mecca Adam P, van Dyck Christopher H, Polimanti Renato

出版信息

medRxiv. 2023 Aug 28:2023.08.25.23294639. doi: 10.1101/2023.08.25.23294639.

DOI:10.1101/2023.08.25.23294639

PMID:37693474

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10491277/

Abstract

BACKGROUND

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.

METHODS

We analyzed a large-scale HD genome-wide association study (GWAS; N = 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 (MRI) modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable (LCV), Mendelian randomization (MR), 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.

RESULTS

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 LCV analyses 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 MR approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→rfMRI-ICA100 node 46 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analyses 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 transcriptomic regulation in females.

CONCLUSION

Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.

摘要

背景

听力障碍（HD）是老年人的主要健康负担之一。虽然外周听觉系统与衰老相关的变化起着重要作用，但与脑结构和功能相关的基因变异也可能与HD易感性有关。

方法

我们分析了一项大规模的HD全基因组关联研究（GWAS；N = 501,825，56%为女性）以及与3935种脑成像衍生表型（IDP）相关的GWAS数据，这些表型在多达33224名个体（52%为女性）中使用多种磁共振成像（MRI）模式进行了评估。为了研究HD与脑结构和功能的多效性，我们进行了遗传相关性、潜在因果变量（LCV）、孟德尔随机化（MR）和多变量广义线性回归分析。此外，我们进行了局部遗传相关性和多性状共定位分析，以确定与HD和脑IDP之间共享的多效性机制相关的基因组区域和位点。

结果

我们观察到在女性中HD与120种IDP、男性中HD与89种IDP以及性别合并分析中HD与171种IDP之间存在广泛的遗传相关性。LCV分析表明，其中一些遗传相关性可能是由于因果关系。对于七种相关性，MR方法也证实了因果效应：在性别合并分析中，血管体积→HD；在女性中，海马体体积→HD、小脑灰质体积→HD、初级视觉皮层体积→HD以及HD→静息态功能磁共振成像独立成分分析100节点46；在男性中，全局平均厚度→HD以及HD→放射冠上部的平均方向离散指数。局部遗传相关性分析确定了HD与这七种IDP之间的13个多效性区域。我们还在女性中观察到HD、初级视觉皮层体积和转录组调控之间的rs13026575变体的共定位信号。