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<p>Rare disease gene discovery is limited by small cohorts and the frequent absence of matched controls. We present the Case-Only Burden Test (COBT), a gene-based burden test for case-only designs accounting for multiple variants per individual and additive effects. COBT uses a Poisson model to test for excess variants in a gene relative to expectations from population mutation rates. Simulations show high power and competitive performance versus case-control burden tests. Validation on 1000 Genomes data demonstrated good model fit and low false-positive rates. Applied to 478 ciliopathy patients, COBT re-identified known causal genes and highlighted candidate variants in unsolved cases.</p>

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COBT: a gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Antoine Favier,
  • Stefania Chounta,
  • Alejandro Garcia,
  • Fabienne Jabot-Hanin,
  • Xiaoyi Chen,
  • Nicolas Garcelon,
  • Anita Burgun,
  • Manuel Higueras,
  • Agathe Guilloux,
  • Alexandre Benmerah,
  • Yoann Martin,
  • Katy Billot,
  • Jean-Michel Rozet,
  • Isabelle Perrault,
  • Valérie Cormier-Daire,
  • Céline Huber,
  • Mohamad Zaidan,
  • Tania Attie-Bitach,
  • Sophie Saunier,
  • Antonio Rausell

摘要

Rare disease gene discovery is limited by small cohorts and the frequent absence of matched controls. We present the Case-Only Burden Test (COBT), a gene-based burden test for case-only designs accounting for multiple variants per individual and additive effects. COBT uses a Poisson model to test for excess variants in a gene relative to expectations from population mutation rates. Simulations show high power and competitive performance versus case-control burden tests. Validation on 1000 Genomes data demonstrated good model fit and low false-positive rates. Applied to 478 ciliopathy patients, COBT re-identified known causal genes and highlighted candidate variants in unsolved cases.