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Alzheimers. Dement., Feb 2025, 21 (2) | https://doi.org/10.1002/alz.14553
Functional insight into East Asian-specific genetic risk loci for Alzheimer's disease
Minyoung Cho1,2,3 Soumilee Chaudhuri1,2,4 Shiwei Liu1,2 Tamina Park1,2 Yen-Ning Huang1,2 Thea Rosewood1,2 Paula J. Bice1 Andrew J. Saykin1,2,4,5 Hong-Hee Won3,6 Kwangsik Nho1,2,7
1 Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA
2 Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
3 Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea
4 Medical Neuroscience Graduate Program, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA
5 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
6 Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
7 School of Informatics and Computing, Indiana University, Indianapolis, Indiana, USA
Correspondence : Hong-Hee Won, Kwangsik Nho
1 Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA
2 Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
3 Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea
4 Medical Neuroscience Graduate Program, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA
5 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
6 Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
7 School of Informatics and Computing, Indiana University, Indianapolis, Indiana, USA
Correspondence : Hong-Hee Won, Kwangsik Nho
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.
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-25)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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