P-617 The investigation of the shared genetic architecture between hypothyroidism and age at menopause

Abstract Study question Is there a shared genetic architecture and a putative causal association between hypothyroidism and age at menopause (AM)? Summary answer There is a genetic correlation and a causal relationship between Hypothyroidism and AM. What is known already Thyroid disease is more common in women. The interplay between thyroid function and the gonadal axes remains interconnected throughout a woman’s reproductive cycle. Notably, the menopausal phase represents a critical period for metabolic alterations, wherein thyroid hormones and metabolic status are intricately intertwined. Study design, size, duration Data from publicly available genome-wide association study (GWAS) summary statistics of hypothyroidism (European-based: 51,194 hypothyroidism cases and 443,383 controls) and AM (European-based: N = 141,926) were used to investigate shared genetic assosiation. Participants/materials, setting, methods Shared genetics between hypothyroidism and AM were explored using linkage disequilibrium score regression, ρ-HESS, cross-trait meta-analysis, colocalization analysis and summary data-based Mendelian randomization, and investigated causal associations using Mendelian randomization. Main results and the role of chance The estimated liability scale of the single nucleotide polymorphisms (SNPs) heritability for AM and hypothyroidism was 13.0% and 5.1%, respectively. A substantial negative genetic association (rg = -0.081, P = 0.0055) was found by bivariate LDSC between hypothyroidism and AM. Local Genetic Correlations identified a strong local signal at 6p21.32-21.33 (chromosome 6: 31571218-32682664) (P = 1.39E-5). Ten important common SNPs were found. Hypothyroidism had a causal effect on AM, but not vice versa. Genetic association between hypothyroidism and AM in blood were enriched in Genotype-Tissue Expression (GTEx) data. In addition, two potentially functional genes, PPM1F and RPL23AP1, were identified to be associated with both hypothyroidism and AM. Limitations, reasons for caution Hypothyroidism encompasses primary and secondary forms, and due to limited data availability, our study could not perform phenotype-specific analyses. Second, even though our research identified genes associated with hypothyroidism and AM, more experimental research and long-term studies are required to fully understand the biological mechanisms underlying the observed genetic relationships. Wider implications of the findings Our study, thorough genome-wide cross-trait analysis, reveals a shared genetic architecture and causal relationship between hypothyroidism and AM. These may open up a new avenue for future research between hypothyroidism and AM. Trial registration number Not applicable