Ancestry-specific genetic effects on urinary 6-sulfatoxymelatonin: a multi-ancestry GWAS meta-analysis

TL;DR

This study explores how genetic factors influence melatonin metabolism across different ancestral groups, revealing ancestry-specific genetic effects and their links to diabetes and sleep.

Contribution

The first multi-ancestry GWAS of urinary 6-sulfatoxymelatonin, highlighting ancestry-specific genetic effects and their metabolic and circadian implications.

Findings

No genome-wide significant loci were identified, but 23 loci showed suggestive significance.

Two loci (SLIT3 rs1875972 and C12orf55 rs7137724) showed ancestry-specific heterogeneity.

Polygenic risk scores linked aMT6s genetics to type 2 diabetes and sleep duration.

Abstract

Melatonin regulates circadian rhythms, metabolism, and immunity. Its primary metabolite, 6-sulfatoxymelatonin (aMT6s), is a biomarker linked to cancer risk and metabolic disorders. However, genetic determinants of aMT6s remain poorly understood, with only one prior GWAS limited to an East Asian cohort.

We conducted the first multi-ancestry genome-wide association meta-analysis of urinary aMT6s, integrating 11,744 participants from five cohorts: East Asians (Taiwan Biobank), European women (Nurses’ Health Studies), European men (MrOS), and multiethnic participants (MEC). aMT6s was measured from overnight or first-morning urine samples. Analyses used MR-MEGA and fixed-effects models in METAL. Polygenic risk scores (PRS) were constructed with PRS-CSx and tested for phenome-wide associations in the Mass General Brigham Biobank and UK Biobank.

No genome-wide significant loci were identified, and previously reported East Asian signals were not replicated. At suggestive significance, 23 loci emerged, with eight supported by both MR-MEGA and METAL. Two loci (SLIT3 rs1875972 and C12orf55 rs7137724) showed ancestry-specific heterogeneity, underscoring the role of population context. PRS analyses revealed robust associations with type 2 diabetes and sleep duration, linking aMT6s genetics to metabolic and circadian traits.

These findings highlight context-dependent genetic architecture of melatonin metabolism and emphasize the importance of ancestry in interpreting biomarker GWAS.

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