Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and senile systemic amyloidoses

Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of senile systemic amyloidosis (SSA). To understand the genetics of ATTRm and SSA, 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 SSA such as chronic ischaemic heart disease (rs140226130, p=2.00x10-6), heart failure (rs73956431, p=2.74x10-6), atrial fibrillation (rs10163755, p=4.63x10-6), dysphagia (rs2949506, p=3.95x10-6), intestine diseases (rs970866, p=7.14x10-6) and anxiety (rs554521234, p=8.85x10-6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p=6.41x10-6) and mononeuropathies of upper limbs (p=1.22x10-5). Sex differences were also observed in line with ATTRm and SSA 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 SSA based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.