| Title: | Ancestry-specific genetic effects on urinary 6-sulfatoxymelatonin: a multi-ancestry GWAS meta-analysis |
| Journal: | - |
| Published: | 1 Oct 2025 |
| DOI: | https://doi.org/10.21203/rs.3.rs-7723851/v1 |
| URL: | https://www.researchsquare.com/article/rs-7723851/latest.pdf |
Publication 19327
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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.</p>
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.</p>
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.</p>
These findings highlight context-dependent genetic architecture of melatonin metabolism and emphasize the importance of ancestry in interpreting biomarker GWAS.</p></p>
23 Authors
- Magdalena Żebrowska
- Ziwei Zhang
- Gwo-Tsann Chuang
- Daniel S Evans
- Jesse Valliere
- Matthew Maher
- Jie Hu
- Rebecca Richmond
- Constance Turman
- Jaime E Hart
- Jacqueline Lane
- Loic Le Marchand
- Lynne Wilkens
- Matthias Wielscher
- Christopher Haiman
- Iona Cheng
- A Heather Eliassen
- Katie L Stone
- Gregory J Tranah
- Yi-Cheng Chang
- Lorelei Ann Mucci
- Eva S Schernhammer
- Richa Saxena
1 Application
| Application ID | Title |
|---|---|
| 48576 | A multi-polygenic score of clock resilience and its utility in predicting vulnerability to night work with regards to chronic disease risk (cardiovascular disease, type 2 diabetes, depression, breast) |
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