A genome-wide association study identifies a novel East Asian–specific locus for dementia with Lewy bodies in Japanese subjects

Background Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent g...

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Published in:Molecular medicine (Cambridge, Mass.) Vol. 31; no. 1; pp. 87 - 11
Main Authors: Mitsumori, Risa, Asanomi, Yuya, Morizono, Takashi, Shigemizu, Daichi, Niida, Shumpei, Ozaki, Kouichi
Format: Journal Article
Language:English
Published: London BioMed Central 06.03.2025
BMC
Subjects:
Aged
Aged, 80 and over
Biomedical and Life Sciences
Biomedicine
Case-Control Studies
Dementia with Lewy bodies
East Asian People - genetics
Expression quantitative trait locus analysis
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Japan
Lewy Body Disease - genetics
Male
Molecular Medicine
Polymorphism, Single Nucleotide
Trans-Ethnic meta-Analysis
Transcriptome-Wide association analysis
Japan
Transcriptome-Wide association analysis
Trans-Ethnic meta-Analysis
Expression quantitative trait locus analysis
Genome-Wide association study
Dementia with Lewy bodies
ISSN:1528-3658, 1076-1551, 1528-3658
Online Access:Get full text
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Summary:Background Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. Methods We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. Results We identified the East Asian–specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P  = 3.27 × 10 –8 ) and the ICOS / PARD3B locus on chromosome 2 with suggestive significance ( P  = 3.95 × 10 –7 ) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P  < 5.0 × 10 –8 ), a known risk locus for DLB and Alzheimer’s disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. Conclusions This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.
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ISSN:1528-3658
1076-1551
1528-3658
DOI:10.1186/s10020-025-01115-7