Minyoung Cho, Soumilee Chaudhuri, Shiwei Liu, Tamina Park, Yen-Ning Huang, Thea Rosewood, Paula J. Bice, Andrew J. Saykin, Hong-Hee Won, Kwangsik Nho
{"title":"Functional insight into East Asian–specific genetic risk loci for Alzheimer's disease","authors":"Minyoung Cho, Soumilee Chaudhuri, Shiwei Liu, Tamina Park, Yen-Ning Huang, Thea Rosewood, Paula J. Bice, Andrew J. Saykin, Hong-Hee Won, Kwangsik Nho","doi":"10.1002/alz.14553","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification of potential therapeutic targets. Investigating AD-associated genetic loci identified in East Asian populations using single-nucleus RNA-sequencing data may identify novel functional genetic contributors.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Cell type–specific expression quantitative trait loci (eQTL) and peak-to-gene links were used to identify functional genes associated with 26 genetic loci from seven genome-wide association studies (GWAS) for AD in East Asians.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p><i>KCNJ6</i> and <i>MAPK1IP1L</i> were identified as significant eQTLs with AD risk loci. AD risk loci were in peaks related to four genes, with <i>CLIC4</i> being connected across different cell types. Genes identified in European and East Asian GWAS interacted within networks and were enriched in AD pathology pathways in astrocytes.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our findings suggest <i>KCNJ6</i> and <i>CLIC4</i> as novel AD-associated functional genes, providing insight into the genetic architecture of AD in East Asians.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Integrated functional analysis of Alzheimer's disease (AD) loci in seven East Asian genome-wide association studies (GWAS) was performed.</li>\n \n <li>Cell type–specific expression quantitative trait loci (eQTLs) and assay for transposase-accessible chromatin peaks were used to identify AD functional genes.</li>\n \n <li>An AD risk variant was linked to <i>KCNJ6</i> through an oligodendrocyte progenitor cell–specific eQTL.</li>\n \n <li>An AD risk variant maps to open chromatin, linked to <i>CLIC4</i> across six cell types.</li>\n \n <li>Astrocyte differentially expressed genes by AD pathology are enriched in East Asian and European GWAS genes.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14553","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14553","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
INTRODUCTION
The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification of potential therapeutic targets. Investigating AD-associated genetic loci identified in East Asian populations using single-nucleus RNA-sequencing data may identify novel functional genetic contributors.
METHODS
Cell type–specific expression quantitative trait loci (eQTL) and peak-to-gene links were used to identify functional genes associated with 26 genetic loci from seven genome-wide association studies (GWAS) for AD in East Asians.
RESULTS
KCNJ6 and MAPK1IP1L were identified as significant eQTLs with AD risk loci. AD risk loci were in peaks related to four genes, with CLIC4 being connected across different cell types. Genes identified in European and East Asian GWAS interacted within networks and were enriched in AD pathology pathways in astrocytes.
DISCUSSION
Our findings suggest KCNJ6 and CLIC4 as novel AD-associated functional genes, providing insight into the genetic architecture of AD in East Asians.
Highlights
Integrated functional analysis of Alzheimer's disease (AD) loci in seven East Asian genome-wide association studies (GWAS) was performed.
Cell type–specific expression quantitative trait loci (eQTLs) and assay for transposase-accessible chromatin peaks were used to identify AD functional genes.
An AD risk variant was linked to KCNJ6 through an oligodendrocyte progenitor cell–specific eQTL.
An AD risk variant maps to open chromatin, linked to CLIC4 across six cell types.
Astrocyte differentially expressed genes by AD pathology are enriched in East Asian and European GWAS genes.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
