Genome- and transcriptome-wide splicing associations with alcohol use disorder.
Genome- and transcriptome-wide splicing associations with alcohol use disorder.
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DOI：
10.1038/s41598-023-30926-z
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发表时间：
2023-03-09
影响因子：
4.6
通讯作者：
Palmer, Rohan H. C.
中科院分区：
文献类型：
--
作者：
Huggett, Spencer B.;Ikeda, Ami S.;Yuan, Qingyue;Benca-Bachman, Chelsie E.;Palmer, Rohan H. C.
大脑中已显示出多种神经精神特征的选择性信使核糖核酸剪接的遗传机制，但不是物质使用障碍。我们的研究使用了关于酒精使用障碍(AUD)的四个大脑区域(n = 56；年龄40-73；100%高加索人；PFC，NAC，BLA和CEA)的rna测序数据和关于AUD的全基因组关联数据(n = 435,563，年龄22-90；100%欧洲裔美国人)。AUD的多基因评分与AUD相关的脑内选择性mRNA剪接相关。我们鉴定了AUD和对照组之间的714个差异剪接基因，其中包括假定的成瘾基因和新的基因靶点。我们发现了6463个与澳大利亚差异剪接基因连锁的剪接数量性状基因座(SQTL)。SQTL主要集中在松散的染色质基因组区域和下游基因靶点。此外，与AUD相关的差异剪接基因内及其周围的DNA变异也丰富了AUD的遗传力。我们的研究还对AUD和其他药物使用特征进行了剪接转录全组关联研究(TWASs)，揭示了用于后续研究的特定基因和跨肥皂的剪接相关性。最后，我们发现，AUD和对照组之间的差异剪接基因也与类似大脑区域的长期饮酒的灵长类动物模型有关。我们的研究发现，在AUD中，选择性信使核糖核酸剪接具有显著的遗传贡献。
Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study utilized RNA-sequencing data on alcohol use disorder (AUD) in four brain regions (n = 56; ages 40–73; 100% ‘Caucasian’; PFC, NAc, BLA and CEA) and genome-wide association data on AUD (n = 435,563, ages 22–90; 100% European-American). Polygenic scores of AUD were associated with AUD-related alternative mRNA splicing in the brain. We identified 714 differentially spliced genes between AUD vs controls, which included both putative addiction genes and novel gene targets. We found 6463 splicing quantitative trait loci (sQTLs) that linked to the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of AUD was enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of AUD and other drug use traits that unveiled specific genes for follow-up and splicing correlations across SUDs. Finally, we showed that differentially spliced genes between AUD vs control were also associated with primate models of chronic alcohol consumption in similar brain regions. Our study found substantial genetic contributions of alternative mRNA splicing in AUD.
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