Abstract
Background The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analytical framework that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the plausibility of there being a causal pathway from genetic variant to complex trait. We demonstrate the value of this approach by investigating association signals detected in a population of young individuals.
Results Eight genetic loci were associated with changes in gene expression and early life measures of cardiovascular function. Fine mapping was undertaken to identify potential causal variants at each region. Our Mendelian randomization analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol respectively were particularly insightful. Multiple trait colocalization uncovered evidence which suggested that changes in DNA methylation at promoter regions upstream of these genes may also play a role in cardiovascular trait variation along with gene expression.
Conclusions Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. Our analytical framework should prove valuable in elucidating mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-expressed. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.
Abbreviations
- GWAS
- Genome-wide association study
- LDL
- Low-density lipoprotein
- SNP
- Single nucleotide polymorphism
- mRNA
- Messenger ribonucleic acid
- eQTL
- Expression quantitative trait loci
- Mb
- Megabase
- TSS
- Transcription start site
- TWAS
- Transcription-wide association study
- MR
- Mendelian Randomization
- GTEx
- Genotype tissue expression project
- LD
- Linkage Disequilibrium
- Moloc
- Multiple-trait colocalization
- mQTL
- Methylation quantitative trait loci
- ALSPAC
- Avon Longitudinal Study of Parents and Children
- ApoB
- Apolipoprotein B
- VLDL
- Very low-density lipoprotein
- PPA
- Posterior probability of association
- BMI
- Body mass index
- IL-6
- Interleukin 6
- ARIES
- Accessible resource for integrated epigenomic studies
- ApoA1
- Apolipoprotein A1
- MAF
- Minor allele frequency
- CRP
- C-Reactive protein