The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic transthyretin expression

Abstract

Transthyretin (TTR) is the precursor of the fibrils that compromise organ function in hereditary and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. In the present study, we leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the Genotype-Tissue Expression project to test the association of genetically regulated TTR gene expression with 7149 traits assessed in 420,531 individuals. We conducted a multi-tissue analysis of TTR transcription and identified an association with a operational procedure related to bone fracture (p = 5.46×10⁻⁶). Using tissue-specific TTR expression information, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, p = 9.51×10⁻⁵). Using the UK Biobank electronic health records (EHRs), we investigated the comorbidities affecting individuals undergoing this surgical procedure. Excluding bone fracture EHRs, we identified a pattern of health outcomes previously associated with ATTR manifestations. These included osteoarthritis (OR = 3.18, p = 9.18×10⁻⁸), carpal tunnel syndrome (OR = 2.15, p = .002), and a history of gastrointestinal diseases (OR = 2.01, p = 8.07×10⁻⁴). In conclusion, our study supports that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein.

Keywords:

• Amyloidosis
• gene expression
• phenome-wide association study
• retinol
• thyroxine
• TTR
• UK Biobank

Acknowledgements

This research has been conducted using the UK Biobank Resource (application reference no. 58146). We thank the research groups contributing to the GTEx Project and the Pan-UKB analysis for making their data publicly available.

Disclosure statement

ADL is supported by a grant from Pfizer. DJ has served as consultant and steering committee member for MyoKardia, Inc. EJM reports grants from Bracco and Eidos, and consulting for General Electric, Alnylam, and Pfizer. RP received a research grant from Pfizer. The other authors declare no conflict of interest.

Data availability statement

All data discussed in this study are provided in the article and in the Supplementary Material.

Additional information

Funding

This study was funded by a research grant from the Amyloidosis Foundation. The authors also acknowledge support from the National Institutes of Health [R21 DC018098, R33 DA047527, and F32 MH122058], the European Commission [H2020 Marie Sklodowska-Curie Individual Fellowship 101028810], and Pfizer [ATTR-PN grant 61031847]. The funders had no role in the study design, data analysis, and data interpretation of the present study.