Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. However, the AD mechanism has not yet been fully elucidated to date, hindering the development of effective therapies. In our work, we perform a brain imaging genomics study to link genetics, single-cell gene express...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | NeuroImage |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1053811923004974 |
| _version_ | 1797683212903776256 |
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| author | Jingxuan Bao Junhao Wen Zixuan Wen Shu Yang Yuhan Cui Zhijian Yang Guray Erus Andrew J. Saykin Qi Long Christos Davatzikos Li Shen |
| author_facet | Jingxuan Bao Junhao Wen Zixuan Wen Shu Yang Yuhan Cui Zhijian Yang Guray Erus Andrew J. Saykin Qi Long Christos Davatzikos Li Shen |
| author_sort | Jingxuan Bao |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. However, the AD mechanism has not yet been fully elucidated to date, hindering the development of effective therapies. In our work, we perform a brain imaging genomics study to link genetics, single-cell gene expression data, tissue-specific gene expression data, brain imaging-derived volumetric endophenotypes, and disease diagnosis to discover potential underlying neurobiological pathways for AD. To do so, we perform brain-wide genome-wide colocalization analyses to integrate multidimensional imaging genomic biobank data. Specifically, we use (1) the individual-level imputed genotyping data and magnetic resonance imaging (MRI) data from the UK Biobank, (2) the summary statistics of the genome-wide association study (GWAS) from multiple European ancestry cohorts, and (3) the tissue-specific cis-expression quantitative trait loci (cis-eQTL) summary statistics from the GTEx project. We apply a Bayes factor colocalization framework and mediation analysis to these multi-modal imaging genomic data. As a result, we derive the brain regional level GWAS summary statistics for 145 brain regions with 482,831 single nucleotide polymorphisms (SNPs) followed by posthoc functional annotations. Our analysis yields the discovery of a potential AD causal pathway from a systems biology perspective: the SNP chr10:124165615:G>A (rs6585827) mutation upregulates the expression of BTBD16 gene in oligodendrocytes, a specialized glial cells, in the brain cortex, leading to a reduced risk of volumetric loss in the entorhinal cortex, resulting in the protective effect on AD. We substantiate our findings with multiple evidence from existing imaging, genetic and genomic studies in AD literature. Our study connects genetics, molecular and cellular signatures, regional brain morphologic endophenotypes, and AD diagnosis, providing new insights into the mechanistic understanding of the disease. Our findings can provide valuable guidance for subsequent therapeutic target identification and drug discovery in AD. |
| first_indexed | 2024-03-12T00:11:18Z |
| format | Article |
| id | doaj.art-a1c9974470b342f383526495380eba11 |
| institution | Directory Open Access Journal |
| issn | 1095-9572 |
| language | English |
| last_indexed | 2024-03-12T00:11:18Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | NeuroImage |
| spelling | doaj.art-a1c9974470b342f383526495380eba112023-09-16T05:28:56ZengElsevierNeuroImage1095-95722023-10-01280120346Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's diseaseJingxuan Bao0Junhao Wen1Zixuan Wen2Shu Yang3Yuhan Cui4Zhijian Yang5Guray Erus6Andrew J. Saykin7Qi Long8Christos Davatzikos9Li Shen10Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USACenter for Biomedical Image Computing and Analytics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Laboratory of AI and Biomedical Science, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, CA 90292, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USACenter for Biomedical Image Computing and Analytics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USACenter for Biomedical Image Computing and Analytics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USACenter for Biomedical Image Computing and Analytics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USACenter for Biomedical Image Computing and Analytics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author.Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. However, the AD mechanism has not yet been fully elucidated to date, hindering the development of effective therapies. In our work, we perform a brain imaging genomics study to link genetics, single-cell gene expression data, tissue-specific gene expression data, brain imaging-derived volumetric endophenotypes, and disease diagnosis to discover potential underlying neurobiological pathways for AD. To do so, we perform brain-wide genome-wide colocalization analyses to integrate multidimensional imaging genomic biobank data. Specifically, we use (1) the individual-level imputed genotyping data and magnetic resonance imaging (MRI) data from the UK Biobank, (2) the summary statistics of the genome-wide association study (GWAS) from multiple European ancestry cohorts, and (3) the tissue-specific cis-expression quantitative trait loci (cis-eQTL) summary statistics from the GTEx project. We apply a Bayes factor colocalization framework and mediation analysis to these multi-modal imaging genomic data. As a result, we derive the brain regional level GWAS summary statistics for 145 brain regions with 482,831 single nucleotide polymorphisms (SNPs) followed by posthoc functional annotations. Our analysis yields the discovery of a potential AD causal pathway from a systems biology perspective: the SNP chr10:124165615:G>A (rs6585827) mutation upregulates the expression of BTBD16 gene in oligodendrocytes, a specialized glial cells, in the brain cortex, leading to a reduced risk of volumetric loss in the entorhinal cortex, resulting in the protective effect on AD. We substantiate our findings with multiple evidence from existing imaging, genetic and genomic studies in AD literature. Our study connects genetics, molecular and cellular signatures, regional brain morphologic endophenotypes, and AD diagnosis, providing new insights into the mechanistic understanding of the disease. Our findings can provide valuable guidance for subsequent therapeutic target identification and drug discovery in AD.http://www.sciencedirect.com/science/article/pii/S1053811923004974Alzheimer's diseaseImaging-geneticsMulti-modalityColocalizationMediation analysis |
| spellingShingle | Jingxuan Bao Junhao Wen Zixuan Wen Shu Yang Yuhan Cui Zhijian Yang Guray Erus Andrew J. Saykin Qi Long Christos Davatzikos Li Shen Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease NeuroImage Alzheimer's disease Imaging-genetics Multi-modality Colocalization Mediation analysis |
| title | Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease |
| title_full | Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease |
| title_fullStr | Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease |
| title_full_unstemmed | Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease |
| title_short | Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease |
| title_sort | brain wide genome wide colocalization study for integrating genetics transcriptomics and brain morphometry in alzheimer s disease |
| topic | Alzheimer's disease Imaging-genetics Multi-modality Colocalization Mediation analysis |
| url | http://www.sciencedirect.com/science/article/pii/S1053811923004974 |
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