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<p>Major depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation may be associated with the condition. However, previous DNA methylation studies have, so far, not been widely replicated, suggesting a need for larger meta-analysis studies. Here we conducted a meta-analysis of methylome-wide association analysis for lifetime MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1,846 controls). We identified 15 CpG sites associated with lifetime MD with methylome-wide significance. The methylation score created using the methylome-wide association analysis summary statistics was significantly associated with MD status in an out-of-sample classification analysis (area under the curve 0.53). Methylation score was also associated with five inflammatory markers, with the strongest association found with tumor necrosis factor beta. Mendelian randomization analysis revealed 23 CpG sites potentially causally linked to MD, with 7 replicated in an independent dataset. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system.</p>

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A methylome-wide association study of major depression with out-of-sample case–control classification and trans-ancestry comparison

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月16日

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  • Xueyi Shen,
  • Miruna Barbu,
  • Doretta Caramaschi,
  • Ryan Arathimos,
  • Darina Czamara,
  • Friederike S. David,
  • Anna Dearman,
  • Evelyn Dilkes,
  • Marisol Herrera-Rivero,
  • Floris Huider,
  • Luise Kühn,
  • Kuan-Chen Lu,
  • Teemu Palviainen,
  • Alicia M. Schowe,
  • Gemma Shireby,
  • Antoine Weihs,
  • Chloe C. Y. Wong,
  • Eleanor Davyson,
  • Hannah Casey,
  • Mark J. Adams,
  • Antje-Kathrin Allgaier,
  • Michael Barber,
  • Joe Burrage,
  • Avshalom Caspi,
  • Ricardo Costeira,
  • Erin C. Dunn,
  • Lisa Feldmann,
  • Josef Frank,
  • Franz J. Freisleder,
  • Danni A. Gadd,
  • Ellen Greimel,
  • Eilis Hannon,
  • Sarah E. Harris,
  • Georg Homuth,
  • David M. Howard,
  • Stella Iurato,
  • Tellervo Korhonen,
  • Tzu-Pin Lu,
  • Nicholas G. Martin,
  • Jade Martins,
  • Edel McDermott,
  • Susanne Meinert,
  • Pau Navarro,
  • Miina Ollikainen,
  • Verena Pehl,
  • Charlotte Piechaczek,
  • Aline D. Scherff,
  • Frederike Stein,
  • Fabian Streit,
  • Alexander Teumer,
  • Henry Völzke,
  • Jenny van Dongen,
  • Rosie M. Walker,
  • Natan Yusupov,
  • Louise Arseneault,
  • Jordana T. Bell,
  • Klaus Berger,
  • Elisabeth Binder,
  • Dorret I. Boomsma,
  • Simon R. Cox,
  • Udo Dannlowski,
  • Kathryn L. Evans,
  • Helen L. Fisher,
  • Andreas J. Forstner,
  • Hans J. Grabe,
  • Jaakko Kaprio,
  • Tilo Kircher,
  • Johannes Kopf-Beck,
  • Meena Kumari,
  • Po-Hsiu Kuo,
  • Qingqin S. Li,
  • Terrie E. Moffitt,
  • Hugh Mulcahy,
  • Therese M. Murphy,
  • Gerd Schulte-Körne,
  • Jonathan Mill,
  • Cathryn M. Lewis,
  • Jenny van Dongen,
  • Naomi R. Wray,
  • Andrew M. McIntosh

摘要

Major depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation may be associated with the condition. However, previous DNA methylation studies have, so far, not been widely replicated, suggesting a need for larger meta-analysis studies. Here we conducted a meta-analysis of methylome-wide association analysis for lifetime MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1,846 controls). We identified 15 CpG sites associated with lifetime MD with methylome-wide significance. The methylation score created using the methylome-wide association analysis summary statistics was significantly associated with MD status in an out-of-sample classification analysis (area under the curve 0.53). Methylation score was also associated with five inflammatory markers, with the strongest association found with tumor necrosis factor beta. Mendelian randomization analysis revealed 23 CpG sites potentially causally linked to MD, with 7 replicated in an independent dataset. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system.