Department of Computer Science: MSc Thesis Presentation

Date: Monday, 27 June 2022
Time: 14:00-14:30
Place: https://aalto.zoom.us/j/67781565167

Characterization of the Liver Transcriptome and its Genetic Regulation

Author: Emilia Vartiainen
Supervisor: Juho Rousu
Advisor: Taru Tukiainen, University of Helsinki

Abstract:

Finland has a unique genetic structure due its history of several bottleneck events which have enabled the FinnGen study to originate. FinnGen performs, among other things, genome-wide association studies (GWASs) to identify associations between variants and phenotypes, such as diseases like intrahepatic cholestasis of pregnancy (ICP) with a perspective on Finnish-enriched variants. However, GWAS results on their own are not completely competence and they need follow up analysis to be able to infer the exact disease-causal variants.

Studying and understanding the transcriptome, the total set of RNA transcripts in a cell, is essential for interpreting the molecular and functional elements of the genome, in order to identify the mechanisms of complex traits and diseases such as ICP. Expression quantitative trait loci (eQTLs), on the other hand, are variants associated with affecting the expression levels of a gene. These eQTL and GWAS results can be integrated via a method called colocalization analysis in order to identify the shared causal variants between the two traits to find potential molecular mechanisms underlying disease associations.

This thesis aims to characterize a Finnish liver transcriptome and its genetic regulation, as well as tointegrate the Finnish liver eQTLs with Finnish GWAS results via colocalization analysis in order to facilitate functional genomics follow up on Finnish-specific GWAS discoveries. This was done by designing and implementing an RNA-seq analysis pipeline to process a collection of 136 Finnish liver (FinnLiver) RNA-seq samples.

As a result, the primary analyses elucidated that the liver samples are reflective of liver tissue's transcriptome, as was expected. Comparison of the FinnLiver eQTLs with GTEx liver showed that, while the majority of the eQTLs were concordant (77.7\%) between the two data, 22.3\% of them were significant only in either data and insignificant in the other. Integrating the eQTLs with Finnish ICP GWAS-results revealed 7 genes having colocalization of which 4 are also significant in GTEx liver and ICP colocalization results, while 3 genes are independent to FinnLiver and ICP. The 4 genes (HKDC1, TMEM147, SULT2A1 and LINC01595) could thus be possible causal genes for ICP, whereas the 3 genes (ABCG8, UBXN2B and C2orf16), especially ABCG8, could have Finnish-enriched variants though they do need further investigation.