Research squareNov 24, 2025

Genetic differences by ancestry linked to levels of a melatonin breakdown product in urine

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 15, 2026

Abstract

A total of 11,744 participants were integrated from five cohorts to analyze genetic determinants of the biomarker 6-sulfatoxymelatonin (aMT6s).

No genome-wide significant genetic loci for aMT6s were identified in the multi-ancestry analysis.
Twenty-three loci emerged at suggestive significance, with eight supported by multiple analytical methods.
Two loci displayed ancestry-specific genetic differences, indicating the influence of population context on aMT6s genetics.
Polygenic risk scores showed strong associations with type 2 diabetes and sleep duration, suggesting links between aMT6s genetics and metabolic traits.
Findings emphasize the importance of considering ancestry when interpreting genetic data related to melatonin metabolism.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

Additional Declarations: No competing interests reported. Disclosure of interest The authors have no relevant financial or non-financial interests to disclose

PubMed

Genetic differences by ancestry linked to levels of a melatonin breakdown product in urine

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief