Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract
IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association st...
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| Format: | Article |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Ophthalmology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fopht.2024.1362350/full |
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| author | Hélène Choquet Matthieu Duot Matthieu Duot Victor A. Herrera Sanjaya K. Shrestha Travis J. Meyers Thomas J. Hoffmann Thomas J. Hoffmann Poorab K. Sangani Salil A. Lachke Salil A. Lachke |
| author_facet | Hélène Choquet Matthieu Duot Matthieu Duot Victor A. Herrera Sanjaya K. Shrestha Travis J. Meyers Thomas J. Hoffmann Thomas J. Hoffmann Poorab K. Sangani Salil A. Lachke Salil A. Lachke |
| author_sort | Hélène Choquet |
| collection | DOAJ |
| description | IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue. |
| first_indexed | 2024-04-24T08:58:09Z |
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| last_indexed | 2025-03-21T00:07:37Z |
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| spelling | doaj.art-fdb6f513d24d481497f15b476de1284a2024-08-03T10:18:13ZengFrontiers Media S.A.Frontiers in Ophthalmology2674-08262024-04-01410.3389/fopht.2024.13623501362350Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataractHélène Choquet0Matthieu Duot1Matthieu Duot2Victor A. Herrera3Sanjaya K. Shrestha4Travis J. Meyers5Thomas J. Hoffmann6Thomas J. Hoffmann7Poorab K. Sangani8Salil A. Lachke9Salil A. Lachke10Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, United StatesDepartment of Biological Sciences, University of Delaware, Newark, DE, United StatesThe National Centre for Scientific Research (CNRS), IGDR (Institut de Génétique et Développement de Rennes) - Joint Research Units (UMR), Univ Rennes, Rennes, FranceKaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, United StatesDepartment of Biological Sciences, University of Delaware, Newark, DE, United StatesKaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, United StatesInstitute for Human Genetics, University of California San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Epidemiology and Biostatistics, UCSF, San Francisco, CA, United StatesDepartment of Ophthalmology, KPNC, South San Francisco, CA, United StatesDepartment of Biological Sciences, University of Delaware, Newark, DE, United StatesCenter for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, United StatesIntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.https://www.frontiersin.org/articles/10.3389/fopht.2024.1362350/fullgeneticsTWAS - transcriptome-wide association studygene expressionlens tissuecataractmulti-tissue analysis |
| spellingShingle | Hélène Choquet Matthieu Duot Matthieu Duot Victor A. Herrera Sanjaya K. Shrestha Travis J. Meyers Thomas J. Hoffmann Thomas J. Hoffmann Poorab K. Sangani Salil A. Lachke Salil A. Lachke Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract Frontiers in Ophthalmology genetics TWAS - transcriptome-wide association study gene expression lens tissue cataract multi-tissue analysis |
| title | Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract |
| title_full | Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract |
| title_fullStr | Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract |
| title_full_unstemmed | Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract |
| title_short | Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract |
| title_sort | multi tissue transcriptome wide association study identifies novel candidate susceptibility genes for cataract |
| topic | genetics TWAS - transcriptome-wide association study gene expression lens tissue cataract multi-tissue analysis |
| url | https://www.frontiersin.org/articles/10.3389/fopht.2024.1362350/full |
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