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

孟德尔随机化 多效性 表型 全基因组关联研究 遗传相关 神经影像学 大脑结构与功能 大脑大小 遗传建筑学 神经科学 数量性状位点 生物 遗传变异 医学 磁共振成像 遗传学 单核苷酸多态性 基因型 遗传变异 基因 放射科
作者
Jun He,Brenda Cabrera‐Mendoza,Flavio De Angelis,Gita A. Pathak,Dóra Koller,Sharon G. Curhan,Gary C. Curhan,Adam P. Mecca,Christopher H. van Dyck,Renato Polimanti
出处
期刊:Brain [Oxford University Press]
卷期号:147 (10): 3395-3408 被引量:3
标识
DOI:10.1093/brain/awae077
摘要

Abstract Hearing difficulty (HD) is a major health burden in older adults. While ageing-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 analysed a large-scale HD genome-wide association study (GWAS; ntotal = 501 825, 56% females) and GWAS data related to 3935 brain imaging-derived phenotypes (IDPs) assessed in up to 33 224 individuals (52% females) using multiple MRI 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 co-localization 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 in males and 171 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 of them, 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 co-localization 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.
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