Integrative multiomics analysis highlights immune-cell regulatory mechanisms and shared genetic architecture for 14 immune-associated diseases and cancer outcomes

Claire Prince, Ruth E Mitchell, Tom G Richardson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
58 Downloads (Pure)

Abstract

Developing functional insight into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here we systematically apply Mendelian randomization (MR), genetic colocalization, immune cell-type enrichment and phenome-wide association methods to investigate the effects of genetically predicted gene expression on 10 immune-associated diseases and 4 cancer outcomes. Using whole blood derived estimates for regulatory variants from the eQTLGen consortium (n=31,684) we constructed genetic risk scores for 10,104 genes. Applying the inverse-variance weighted MR method transcriptome-wide whilst accounting for linkage disequilibrium structure identified 664 unique genes with evidence of a genetically predicted effect on at least one disease outcome (P<4.81 x10-5). We next undertook genetic colocalization to investigate cell-type specific effects at these loci using gene expression data derived from 18 types of immune cells. This highlighted many cell-type dependent effects, such as PRKCQ expression and asthma risk (posterior probability=0.998), which was T-cell specific. Phenome-wide analyses on 311 complex traits and endpoints allowed us to explore shared genetic architecture and prioritize key drivers of disease risk, such as CASP10 which provided evidence of an effect on 7 cancer-related outcomes. Our atlas of results can be used to characterize known and novel loci in immune-associated disease and cancer susceptibility, both in terms elucidating cell-type dependent effects as well as dissecting shared disease pathways and pervasive pleiotropy. As an exemplar, we have highlighted several key findings in this study, although similar evaluations can be conducted using our interactive web platform.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Publication statusPublished - 5 Nov 2021

Keywords

  • immune-associated disease
  • cancer epidemiology
  • transcriptome-wide
  • cell-type specificity
  • Mendelian randomization
  • genetic colocalization

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