Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder
Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder
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基于表观遗传元件的转录组范围关联研究鉴定出双相情感障碍的新基因
DOI：
10.1093/schbul/sbab023
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发表时间：
2020-07
影响因子：
6.6
通讯作者：
Yan Guo
中科院分区：
文献类型：
--
作者：
Shi Yao;Hao Wu;Tong-Tong Liu;Jia-Hao Wang;Jing-Miao Ding;Jing Guo;Yu Rong;Xin Ke;Ruo-Han Hao;Shan-Shan Dong;Tie-Lin Yang;Yan Guo
抽象。由于全基因组关联研究（GWAS）发现的双相情感障碍（BD）信号通常位于非编码区，因此理解这些遗传位点的生物学相关性已被证明是复杂的。全转录组关联研究（TWAS）提供了一种强有力的方法来识别新的疾病风险基因，并发现先前由GWAS确定的基因座上可能的致病基因。然而，这些方法没有考虑表观遗传调控在基因表达中的重要性。在这里，我们开发了一种新的基于表观遗传元件的全转录组关联研究（ETWAS），该研究以表观遗传特征为先验，测试了遗传变异对基因表达水平的影响，并进一步介导了预测表达与BD之间的关联。我们进行了一项由20352例病例和31358例对照组成的ETWAS，并确定了44个转录组范围内的显著命中。共发现14个条件独立基因，其中10个与BD无关的基因被认为是新的候选基因，如小脑半球的ASB16（P = 9.29 × 10 - 8）。我们证明了来自BD GWAS的几个全基因组显著信号由遗传调节表达驱动，NEK4解释了90.1%的GWAS信号。此外，ETWAS鉴定的基因可以解释遗传性，超出GWAS相关SNP的解释（P = 5.60 × 10 - 66）。通过查询表型数据库中已识别基因的最终模型中的SNP，我们识别了几种以前与BD相关的表型，例如精神分裂症和抑郁症。总之，ETWAS是一个强大的方法，我们确定了几个新的候选基因与BD。
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.
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影响因子：
4.5
作者：
Manor O;Segal E
通讯作者：
Segal E
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64.8
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作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
30.8
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Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen