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Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder.

ABSTRACT: Since the bipolar disorder (BD) signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expression. Here, we developed a novel epigenetic element-based transcriptome-wide association study (ETWAS) that tested the effects of genetic variants on gene expression levels with the epigenetic features as prior and further mediated the association between predicted expression and BD. We conducted an ETWAS consisting of 20 352 cases and 31 358 controls and identified 44 transcriptome-wide significant hits. We found 14 conditionally independent genes, and 10 genes that did not previously implicate with BD were regarded as novel candidate genes, such as ASB16 in the cerebellar hemisphere (P = 9.29 × 10-8). We demonstrated that several genome-wide significant signals from the BD GWAS driven by genetically regulated expression, and NEK4 explained 90.1% of the GWAS signal. Additionally, ETWAS identified genes could explain heritability beyond that explained by GWAS-associated SNPs (P = 5.60 × 10-66). By querying the SNPs in the final models of identified genes in phenome databases, we identified several phenotypes previously associated with BD, such as schizophrenia and depression. In conclusion, ETWAS is a powerful method, and we identified several novel candidate genes associated with BD.

SUBMITTER: Yao S

PROVIDER: S-EPMC8530404 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder.

Yao Shi S Wu Hao H Liu Tong-Tong TT Wang Jia-Hao JH Ding Jing-Miao JM Guo Jing J Rong Yu Y Ke Xin X Hao Ruo-Han RH Dong Shan-Shan SS Yang Tie-Lin TL Guo Yan Y

Schizophrenia bulletin 20211001 6

Since the bipolar disorder (BD) signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expr ...[more]

PMID: 33772305

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Project 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.

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Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder.

Publications

Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder.

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