Ancestry-specific genetic effects on urinary 6-sulfatoxymelatonin: a multi-ancestry GWAS meta-analysis
Magdalena Żebrowska1, Ziwei Zhang2, Gwo-Tsann Chuang3
1Medical University of Vienna.
Research Square
|November 24, 2025
Summary
Genetic factors influencing 6-sulfatoxymelatonin (aMT6s), a key melatonin metabolite, were explored across diverse ancestries. While no major genetic loci were found, polygenic risk scores linked aMT6s to type 2 diabetes and sleep duration.
Area of Science:
- Genetics
- Metabolomics
- Chronobiology
Background:
- Melatonin is crucial for circadian rhythms, metabolism, and immunity.
- Its metabolite, 6-sulfatoxymelatonin (aMT6s), is a biomarker for cancer and metabolic disorders.
- Genetic underpinnings of aMT6s are largely unknown, with prior studies limited to East Asian populations.
Purpose of the Study:
- To conduct the first multi-ancestry genome-wide association meta-analysis for urinary aMT6s.
- To identify genetic determinants of aMT6s across diverse populations.
- To investigate the association of aMT6s genetic risk scores with phenome-wide traits.
Main Methods:
- Meta-analysis of genome-wide association studies (GWAS) using MR-MEGA and METAL across five cohorts (n=11,744).
- Measurement of aMT6s from urine samples.
- Construction and phenome-wide association testing of polygenic risk scores (PRS) using PRS-CSx in large biobanks.
Main Results:
- No genome-wide significant loci for aMT6s were identified; previously reported East Asian signals were not replicated.
- 23 loci reached suggestive significance, with 8 supported by both analytical methods.
- Two loci exhibited ancestry-specific heterogeneity, highlighting population context.
- PRS analyses demonstrated significant associations between aMT6s genetics and type 2 diabetes and sleep duration.
Conclusions:
- The genetic architecture of melatonin metabolism (aMT6s) is context-dependent and influenced by ancestry.
- Ancestry is critical for interpreting findings from biomarker GWAS.
- Genetic factors related to aMT6s are associated with metabolic and circadian traits.
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