A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

Abstract

Developing insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. In this study, we apply the principles of Mendelian randomization to systematically evaluate transcriptome-wide associations between gene expression (across 48 different tissue types) and 395 complex traits. Our findings indicate that variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. Moreover, detailed investigations of our results highlight tissue-specific associations, drug validation opportunities, insight into the likely causal pathways for trait-associated variants and also implicate putative associations at loci yet to be implicated in disease susceptibility. Similar evaluations can be conducted at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

The COVID-19 Pandemic from a Human Genetic Perspective

“…To address this, recent studies have demonstrated the value of omics studies in predicting the potential effects of a drug target on complex diseases. 37 , 38 Thus, comprehensive assessment of the causal effects of COVID-19 drug targets on disease phenotypes will provide key information regarding their safety issue ( Figure 3 ). 39 …”

A Comprehensive Evaluation of Methods for Mendelian Randomization Using Realistic Simulations and an Analysis of 38 Biomarkers for Risk of Type-2 Diabetes

“…Two-sample MR analysis 4,5 is particularly popular as these methods can be applied even if the genome-wide association study for the different traits are conducted on nonoverlapping samples. In recent years, the growing sample size of GWAS and volume of publicly available summary-level datasets have facilitated the popularization of MR. MR analyses have led to improved understanding of epidemiological associations, discovery of new drug targets 3,6 , and new insights into biological mechanisms through applications to large-scale omics data [7][8][9] .…”

Using Mendelian randomization to understand and develop treatments for neurodegenerative disease

“…Furthermore, another MR study has shown that acetylcholinesterase expression may be causally associated with raised blood pressure ( Richardson et al , 2020 ). ACHE encodes the target for acetylcholinesterase inhibitors such as donepezil and galantamine, which are licenced treatments for Alzheimer’s disease ( Lane et al , 2018 ).…”

“…Tissue diversity has been more thoroughly explored for eQTL data ( Gamazon et al , 2018 ; Taylor et al , 2019 ; Richardson et al , 2020 ). For example, an MR study found that FBN2 expression in heart tissue was linked to diastolic blood pressure, whereas FBN2 expression in lung tissue was linked to forced vital capacity ( Richardson et al , 2020 ). Such evidence suggests that biologically relevant tissues may be crucial for molecular-level MR projects.…”