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Abstract：
UNASSIGNED: Cataract 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.
UNASSIGNED: We 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.
UNASSIGNED: Across 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.
UNASSIGNED: Our 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.
UNASSIGNED: We 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.
UNASSIGNED: Across 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.
UNASSIGNED: Our 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.
摘要：
白内障是全球老年人失明的主要原因。双胞胎和家族研究支持遗传因素在白内障易感性中的重要作用，遗传率估计高达58％。迄今为止,通过全基因组关联研究(GWAS)已经确定了55个白内障基因座，然而,还有很多工作要确定因果基因。这里,我们对白内障进行了全转录组关联研究（TWAS），以确定致病基因的优先级并鉴定新基因，并检查他们表达的影响。
我们使用FUSION软件进行了组织特异性和多组织TWAS分析，以评估来自54个组织（包括来自基因型组织表达（GTEx）项目v8的49个）的估算基因表达与白内障之间的关联。Meta分析了59,944例白内障病例和478,571例对照的GWAS汇总统计数据，使用所有欧洲血统和两个队列(GERA和UKBiobank).然后，我们使用iSyTE数据库检查了晶状体组织中新基因的表达。
■跨组织特异性和多组织分析，我们确定了99个基因,这些基因预测的基因表达在校正多项检测后与白内障相关.在这99个基因中,20(AC007773.1,ANKH,ASIP,ATP13A2,CAPZB,CEP95,COQ6,CREB1,CROCC,DDX5,EFEMP1,EIF2S2,ESRRB,GOSR2HERC4INSRR,NIPSNAP2,PICALM,SENP3和SH3YL1）与先前报道的白内障相关基因座不重叠。组织特异性分析确定了202个明显的白内障基因-组织关联，其中166人（82.2%），代表9个独特的基因，归因于先前报道的11q13.3基因座。组织富集分析显示，胃肠组织代表了Bonferroni显着的基因-组织关联的最高比例之一（21.3％）。此外，这种胃肠道组织类型是我们结果中唯一显着丰富的解剖类别，在校正每个参考组的组织供体数量和可估算基因后。最后,大多数新的白内障基因(例如，Capzb）在iSyTE晶状体数据中稳健表达。
■我们的结果提供了证据，证明了基于归因的TWAS方法可用于表征已知的GWAS风险位点，并鉴定可能增加我们对白内障病因的理解的新候选基因。我们的发现还强调了与白内障易感性相关的基因的表达不一定限于晶状体组织的事实。
我们使用FUSION软件进行了组织特异性和多组织TWAS分析，以评估来自54个组织（包括来自基因型组织表达（GTEx）项目v8的49个）的估算基因表达与白内障之间的关联。Meta分析了59,944例白内障病例和478,571例对照的GWAS汇总统计数据，使用所有欧洲血统和两个队列(GERA和UKBiobank).然后，我们使用iSyTE数据库检查了晶状体组织中新基因的表达。
■跨组织特异性和多组织分析，我们确定了99个基因,这些基因预测的基因表达在校正多项检测后与白内障相关.在这99个基因中,20(AC007773.1,ANKH,ASIP,ATP13A2,CAPZB,CEP95,COQ6,CREB1,CROCC,DDX5,EFEMP1,EIF2S2,ESRRB,GOSR2HERC4INSRR,NIPSNAP2,PICALM,SENP3和SH3YL1）与先前报道的白内障相关基因座不重叠。组织特异性分析确定了202个明显的白内障基因-组织关联，其中166人（82.2%），代表9个独特的基因，归因于先前报道的11q13.3基因座。组织富集分析显示，胃肠组织代表了Bonferroni显着的基因-组织关联的最高比例之一（21.3％）。此外，这种胃肠道组织类型是我们结果中唯一显着丰富的解剖类别，在校正每个参考组的组织供体数量和可估算基因后。最后,大多数新的白内障基因(例如，Capzb）在iSyTE晶状体数据中稳健表达。
■我们的结果提供了证据，证明了基于归因的TWAS方法可用于表征已知的GWAS风险位点，并鉴定可能增加我们对白内障病因的理解的新候选基因。我们的发现还强调了与白内障易感性相关的基因的表达不一定限于晶状体组织的事实。
