Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis
Abstract Background The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer’s disease (AD) and Parkinson’s disease (PD) remain...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02404-2 |
| _version_ | 1828808782368473088 |
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| author | Ping Guo Weiming Gong Yuanming Li Lu Liu Ran Yan Yanjun Wang Yanan Zhang Zhongshang Yuan |
| author_facet | Ping Guo Weiming Gong Yuanming Li Lu Liu Ran Yan Yanjun Wang Yanan Zhang Zhongshang Yuan |
| author_sort | Ping Guo |
| collection | DOAJ |
| description | Abstract Background The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer’s disease (AD) and Parkinson’s disease (PD) remain poorly understood. Methods Using the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms. Results Pairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10−2). Conclusions Our findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously. |
| first_indexed | 2024-12-12T08:46:12Z |
| format | Article |
| id | doaj.art-9be42cc0e2cd45218848b701ebc7ca96 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-12T08:46:12Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj.art-9be42cc0e2cd45218848b701ebc7ca962022-12-22T00:30:31ZengBMCBMC Medicine1741-70152022-06-0120111610.1186/s12916-022-02404-2Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysisPing Guo0Weiming Gong1Yuanming Li2Lu Liu3Ran Yan4Yanjun Wang5Yanan Zhang6Zhongshang Yuan7Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversitySchool of Medicine, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong UniversityAbstract Background The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer’s disease (AD) and Parkinson’s disease (PD) remain poorly understood. Methods Using the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms. Results Pairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10−2). Conclusions Our findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously.https://doi.org/10.1186/s12916-022-02404-2Lewy body dementiaAlzheimer’s diseaseParkinson’s diseaseShared geneticsMulti-trait association analysis |
| spellingShingle | Ping Guo Weiming Gong Yuanming Li Lu Liu Ran Yan Yanjun Wang Yanan Zhang Zhongshang Yuan Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis BMC Medicine Lewy body dementia Alzheimer’s disease Parkinson’s disease Shared genetics Multi-trait association analysis |
| title | Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis |
| title_full | Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis |
| title_fullStr | Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis |
| title_full_unstemmed | Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis |
| title_short | Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis |
| title_sort | pinpointing novel risk loci for lewy body dementia and the shared genetic etiology with alzheimer s disease and parkinson s disease a large scale multi trait association analysis |
| topic | Lewy body dementia Alzheimer’s disease Parkinson’s disease Shared genetics Multi-trait association analysis |
| url | https://doi.org/10.1186/s12916-022-02404-2 |
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