通过结合定量和生存特征分析鉴定阿尔茨海默病发病年龄的新基因。

Identification of novel genes for age-at-onset of Alzheimer's disease by combining quantitative and survival trait analyses.

机构信息

Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA.

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.

出版信息

Alzheimers Dement. 2023 Jul;19(7):3148-3157. doi: 10.1002/alz.12927. Epub 2023 Feb 4.

DOI:10.1002/alz.12927

PMID:36738287

Abstract

INTRODUCTION

Our understanding of the genetic predisposition for age-at-onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex-specific effects.

METHODS

Genome-wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome.

RESULTS

We identified 11 genome-wide significant loci (P < 5 × 10 ), including six known AD-risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex-specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males.

DISCUSSION

Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.

摘要

简介

我们对阿尔茨海默病（AD）发病年龄（AAO）的遗传易感性了解有限。在此，我们试图确定修饰 AAO 的基因，并研究是否存在性别特异性效应。

方法

对来自 20 个阿尔茨海默病遗传学联合会队列的 9219 例 AD 病例和 10345 例对照的经推断的遗传数据进行全基因组关联分析。直接从病例中以及作为生存结果来模拟 AAO。

结果

我们确定了 11 个全基因组显著位点（P<5×10），包括六个已知的 AD 风险基因和五个新的位点，UMAD1、LUZP2、ARFGEF2、DSCAM 和 4q25，这些都影响 AD 的 AAO。此外，39 个提示性位点显示出强烈的关联。有 12 个位点对 AAO 具有性别特异性影响，包括女性的 CD300LG 和 MLX/TUBG2，以及男性的 MIR4445。