Scholarlink

<p>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. Association analyses were conducted using both ancestry-aware meta-regression (MR-MEGA) and fixed-effects meta-analysis (METAL). Polygenic risk scores (PRS) were constructed with PRS-CSx and evaluated in phenome-wide analyses 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. Several loci showed ancestry-specific heterogeneity, suggesting that genetic associations with urinary aMT6s may vary by population context, although limited power and cohort heterogeneity may also contribute. PRS analyses identified associations with sleep duration and metabolic traits, including type 2 diabetes, but these findings require cautious interpretation. Overall, our results suggest that urinary aMT6s is influenced by a polygenic and potentially population-dependent genetic architecture. This study provides a multi-ancestry framework for investigating melatonin-related biomarkers and highlights the importance of careful interpretation across diverse populations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Multi ancestry genome wide association meta analysis of urinary aMT6s levels

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月22日

查看全文
  • 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

摘要

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. Association analyses were conducted using both ancestry-aware meta-regression (MR-MEGA) and fixed-effects meta-analysis (METAL). Polygenic risk scores (PRS) were constructed with PRS-CSx and evaluated in phenome-wide analyses 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. Several loci showed ancestry-specific heterogeneity, suggesting that genetic associations with urinary aMT6s may vary by population context, although limited power and cohort heterogeneity may also contribute. PRS analyses identified associations with sleep duration and metabolic traits, including type 2 diabetes, but these findings require cautious interpretation. Overall, our results suggest that urinary aMT6s is influenced by a polygenic and potentially population-dependent genetic architecture. This study provides a multi-ancestry framework for investigating melatonin-related biomarkers and highlights the importance of careful interpretation across diverse populations.