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<p>Understanding the genetic regulation of RNA abundance is essential for defining disease mechanisms. Conventional expression quantitative trait locus (eQTL) studies measure steady-state RNA and capture effects across the entire transcript lifecycle. While most eQTL likely affect transcription by altering promoter or enhancer function within the nucleus, others may act post-transcriptionally through RNA modification or stability in the cytosol. To distinguish these mechanisms, we compare eQTL from mature cellular RNA and recently transcribed nuclear RNA in brain and kidney. We identify distinct causal variants underlying cellular and nuclear eQTL at the same <i>eGene</i>s. Cellular eQTL are enriched in transcribed regions (P = 3.3×10⁻¹²⁶), suggesting post-transcriptional regulation, whereas nuclear eQTL are enriched in distal regulatory elements (P = 7.0×10⁻³²), consistent with transcriptional control. For example, stop-gain variants likely acting through nonsense-mediated decay appear only in cellular eQTL. Conversely, nuclear eQTL variants (e.g., <i>TUBGCP4</i>) within enhancers sometimes uniquely colocalize with disease loci (schizophrenia), revealing distinct regulatory mechanisms.</p>

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Early and late RNA eQTL are driven by different genetic mechanisms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月25日

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  • Saori Sakaue,
  • Jennifer H. Anolik,
  • William Apruzzese,
  • Arnon Arazi,
  • Jennifer L. Barnas,
  • H. Michael Belmont,
  • Celine C. Berthier,
  • Jill P. Buyon,
  • Michelle Curtis,
  • Carla M. Cuda,
  • Maria Dall’Era,
  • Anne Davidson,
  • Betty Diamond,
  • Thomas M. Eisenhaure,
  • Andrea Fava,
  • Jennifer Grossman,
  • Siddarth Gurajala,
  • Joel M. Guthridge,
  • Nir Hacohen,
  • David A. Hildeman,
  • Jeffrey B. Hodgin,
  • Paul J. Hoover,
  • Alice Horsberger,
  • Peter M. Izmirly,
  • Judith A. James,
  • Kenneth C. Kalunian,
  • Diane L. Kamen,
  • Joseph Mears,
  • Maureen A. McMahon,
  • Michael Peters,
  • Michelle A. Petri,
  • Harris Perlman,
  • Chaim Putterman,
  • Deepak A. Rao,
  • Raktima Raychowdhury,
  • Brad Rovin,
  • Fernanda Payan-Schober,
  • Nicholas W. Sugiarto,
  • David Wofsy,
  • E. Steve Woodle,
  • Qian Xiao,
  • Yu Zhao,
  • Soumya Raychaudhuri

摘要

Understanding the genetic regulation of RNA abundance is essential for defining disease mechanisms. Conventional expression quantitative trait locus (eQTL) studies measure steady-state RNA and capture effects across the entire transcript lifecycle. While most eQTL likely affect transcription by altering promoter or enhancer function within the nucleus, others may act post-transcriptionally through RNA modification or stability in the cytosol. To distinguish these mechanisms, we compare eQTL from mature cellular RNA and recently transcribed nuclear RNA in brain and kidney. We identify distinct causal variants underlying cellular and nuclear eQTL at the same eGenes. Cellular eQTL are enriched in transcribed regions (P = 3.3×10⁻¹²⁶), suggesting post-transcriptional regulation, whereas nuclear eQTL are enriched in distal regulatory elements (P = 7.0×10⁻³²), consistent with transcriptional control. For example, stop-gain variants likely acting through nonsense-mediated decay appear only in cellular eQTL. Conversely, nuclear eQTL variants (e.g., TUBGCP4) within enhancers sometimes uniquely colocalize with disease loci (schizophrenia), revealing distinct regulatory mechanisms.