人类海马体的遗传结构及其与神经精神特征相关的遗传结构。

Genetic architectures of the human hippocampus and those involved in neuropsychiatric traits.

机构信息

Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, 430071, China.

Department of Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences of Wuhan University, Wuhan, 430071, China.

出版信息

BMC Med. 2024 Oct 11;22(1):456. doi: 10.1186/s12916-024-03682-8.

DOI:10.1186/s12916-024-03682-8

PMID:39394562

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11470718/

Abstract

BACKGROUND

The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential.

METHODS

We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits.

RESULTS

Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson's disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson's disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18-1.43, P = 6.15 × 10⁻⁸) for right hippocampal volume.

CONCLUSIONS

These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages.

摘要

背景

海马体及其复杂的亚区与众多神经精神特征相关。虽然大多数研究都集中在其整体结构或几个特定的亚区上，但对海马体亚区及其在广泛的神经精神特征中的遗传相关性进行全面分析仍未得到充分探索。鉴于海马体的高遗传性，将海马体和亚区体积（HASV）作为神经精神疾病的表型特征是至关重要的。

方法

我们分析了来自 41525 名英国生物库参与者的 MRI 衍生的海马体和亚区结构的容积数据。对 24 项 HASV 特征进行了全基因组关联研究（GWAS），随后进行了遗传相关性、重叠和与 10 种常见神经精神特征的孟德尔随机化（MR）分析。还评估了基于 HASV 特征的多基因风险评分（PRS），以预测这些特征。

结果

我们的分析确定了 352 个独立的遗传变异，这些变异在 24 项 HASV 特征中超过了 2.1×10 的显著性阈值，位于 93 个染色体区域。值得注意的是，在 12q14.3、17q21.31、12q24.22、6q21、9q33.1、6q25.1 和 2q24.2 区域发现了多个 HASV 影响的位置。基因集分析显示，神经分化和信号通路以及蛋白质结合和降解途径存在富集。在 240 对 HASV-神经精神特征对中，有 75 对表现出显著的遗传相关性（P<0.05/240），揭示了 433 个多效性位点。特别是，ACBD4、ARHGAP27、KANSL1、MAPT、ARL17A 和 ARL17B 等基因与超过 50 个 HASV-神经精神特征对有关。利用孟德尔随机化分析，我们进一步证实左侧海马体、右侧海马体、右侧海马体体部和右侧 CA1-3 区域的萎缩与帕金森病（PD）发病风险增加有关。此外，所有四个 HASV 的 PRS 与帕金森病（PD）的风险增加显著相关，右侧海马体体积的最高危害比（HR）为 1.30（95%CI 1.18-1.43，P=6.15×10⁻⁸）。