Exon expression QTL (eeQTL) analysis highlights distant genomic variations associated with splicing regulation

Guan, Leying; Yang, Qian; Gu, Mengting; Chen, Liang; Zhang, Xuegong

doi:10.1007/s40484-014-0031-9

Cited by 6 publications

(5 citation statements)

References 69 publications

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“…In a large scale human blood cell expression QTLs study [ 12 ], eeQTLs also showed the strongest enrichments of GWAS variants, followed by sQTLs and geQTLs. Thus, focusing on exon-level QTLs, including eeQTLs and sQTLs, could increase the chance of finding regulatory variants for complex traits, as proposed by Guan et al [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues

et al. 2018

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BackgroundMammalian phenotypes are shaped by numerous genome variants, many of which may regulate gene transcription or RNA splicing. To identify variants with regulatory functions in cattle, an important economic and model species, we used sequence variants to map a type of expression quantitative trait loci (expression QTLs) that are associated with variations in the RNA splicing, i.e., sQTLs. To further the understanding of regulatory variants, sQTLs were compare with other two types of expression QTLs, 1) variants associated with variations in gene expression, i.e., geQTLs and 2) variants associated with variations in exon expression, i.e., eeQTLs, in different tissues.ResultsUsing whole genome and RNA sequence data from four tissues of over 200 cattle, sQTLs identified using exon inclusion ratios were verified by matching their effects on adjacent intron excision ratios. sQTLs contained the highest percentage of variants that are within the intronic region of genes and contained the lowest percentage of variants that are within intergenic regions, compared to eeQTLs and geQTLs. Many geQTLs and sQTLs are also detected as eeQTLs. Many expression QTLs, including sQTLs, were significant in all four tissues and had a similar effect in each tissue. To verify such expression QTL sharing between tissues, variants surrounding (±1 Mb) the exon or gene were used to build local genomic relationship matrices (LGRM) and estimated genetic correlations between tissues. For many exons, the splicing and expression level was determined by the same cis additive genetic variance in different tissues. Thus, an effective but simple-to-implement meta-analysis combining information from three tissues is introduced to increase power to detect and validate sQTLs. sQTLs and eeQTLs together were more enriched for variants associated with cattle complex traits, compared to geQTLs. Several putative causal mutations were identified, including an sQTL at Chr6:87392580 within the 5th exon of kappa casein (CSN3) associated with milk production traits.ConclusionsUsing novel analytical approaches, we report the first identification of numerous bovine sQTLs which are extensively shared between multiple tissue types. The significant overlaps between bovine sQTLs and complex traits QTL highlight the contribution of regulatory mutations to phenotypic variations.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4902-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues

et al. 2018

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“…Since most of the known disease-causing mutations occur in exons, genetic methods that focus on protein-coding regions in the genome are effcient in identifying potentially pathogenic mutations (Xue et al, 2019). Therefore, the examination of exons may help us to understand the genetic architecture of SCZ beyond the gene-level (Guan et al, 2014; Ramasamy et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…arrays specifically designed to accurately quantify exons vs RNA sequencing). The accurate quantification of exons is essential to understand the genetic architecture of schizophrenia beyond the gene-level 38,39 .…”

Section: Introductionmentioning

confidence: 99%

Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders

Worf

Matosin

Gerstner

et al. 2022

Preprint

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In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes indicated impaired cell-cell interactions and neuronal activity in psychopathology. With single-nuclei-RNA-sequencing, we pinpointed these effects to inhibitory cortical neurons and oligodendrocyte progenitors, two cell-types that closely interact. This constitutes a clear cellular target for new treatments for psychiatric disorders.

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“…In dairy cattle, Xiang et al [ 12 ] showed that eeQTL overlapped with geQTL and sQTL. Consequently, the combined analysis of geQTL, eeQTL and sQTL may increase the chance to identify loci that regulate gene expression [ 12 , 17 ]. However, to our knowledge, eQTL have not been analyzed in sheep, although it is one of the major farm species for human consumption.…”

Section: Introductionmentioning

confidence: 99%

Expression quantitative trait loci in sheep liver and muscle contribute to variations in meat traits

et al. 2021

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Background Variants that regulate transcription, such as expression quantitative trait loci (eQTL), have shown enrichment in genome-wide association studies (GWAS) for mammalian complex traits. However, no study has reported eQTL in sheep, although it is an important agricultural species for which many GWAS of complex meat traits have been conducted. Using RNA sequence data produced from liver and muscle from 149 sheep and imputed whole-genome single nucleotide polymorphisms (SNPs), our aim was to dissect the genetic architecture of the transcriptome by associating sheep genotypes with three major molecular phenotypes including gene expression (geQTL), exon expression (eeQTL) and RNA splicing (sQTL). We also examined these three types of eQTL for their enrichment in GWAS of multi-meat traits and fatty acid profiles. Results Whereas a relatively small number of molecular phenotypes were significantly heritable (h2 > 0, P < 0.05), their mean heritability ranged from 0.67 to 0.73 for liver and from 0.71 to 0.77 for muscle. Association analysis between molecular phenotypes and SNPs within ± 1 Mb identified many significant cis-eQTL (false discovery rate, FDR < 0.01). The median distance between the eQTL and transcription start sites (TSS) ranged from 68 to 153 kb across the three eQTL types. The number of common variants between geQTL, eeQTL and sQTL within each tissue, and the number of common variants between liver and muscle within each eQTL type were all significantly (P < 0.05) larger than expected by chance. The identified eQTL were significantly (P < 0.05) enriched in GWAS hits associated with 56 carcass traits and fatty acid profiles. For example, several geQTL in muscle mapped to the FAM184B gene, hundreds of sQTL in liver and muscle mapped to the CAST gene, and hundreds of sQTL in liver mapped to the C6 gene. These three genes are associated with body composition or fatty acid profiles. Conclusions We detected a large number of significant eQTL and found that the overlap of variants between eQTL types and tissues was prevalent. Many eQTL were also QTL for meat traits. Our study fills a gap in the knowledge on the regulatory variants and their role in complex traits for the sheep model.

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Exon expression QTL (eeQTL) analysis highlights distant genomic variations associated with splicing regulation

Cited by 6 publications

References 69 publications

Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues

Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues

Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders

Expression quantitative trait loci in sheep liver and muscle contribute to variations in meat traits

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