Abstract
Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of wild-type transthyretin amyloidosis (ATTRwt). To understand the genetics of ATTRm and ATTRwt, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and ATTRwt such as chronic ischaemic heart disease (rs140226130, p = 2.00 × 10−6), heart failure (rs73956431, p = 2.74 × 10−6), atrial fibrillation (rs10163755, p = 4.63 × 10−6), dysphagia (rs2949506, p = 3.95 × 10−6), intestine diseases (rs970866, p = 7.14 × 10−6) and anxiety (rs554521234, p = 8.85 × 10−6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p = 6.41 × 10−6) and mononeuropathies of upper limbs (p = 1.22 × 10−5). Sex differences were also observed in line with ATTRm and ATTRwt epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.
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Data availability
Data supporting the findings of this study are available within this article and its additional files. UK Biobank GWAS summary association data are available at https://github.com/Nealelab/UK_Biobank_GWAS/tree/master/imputed-v2-gwas.
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Acknowledgements
We thank the participants and investigators of the UK Biobank and the Neale lab for generating the genome-wide data used in the present study. This work was partially supported by the PhD Program of the University of Rome Tor Vergata (ADL) and the Yale University School of Medicine (RP). The sources of funding had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
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Drs. Fuciarelli and Polimanti are both receiving research grants from Pfizer Inc. to conduct epigenetic studies of TTR amyloidosis. The other authors reported no biomedical financial interests or potential conflicts of interest.
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This study was conducted using summary association data generated by previous studies. Owing to the use of previously collected, deidentified, aggregated data, this study did not require institutional review board approval.
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De Lillo, A., De Angelis, F., Di Girolamo, M. et al. Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses. Hum Genet 138, 1331–1340 (2019). https://doi.org/10.1007/s00439-019-02078-6
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DOI: https://doi.org/10.1007/s00439-019-02078-6