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<p>We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham Heart Study (FHS, <i>n</i> = 2622) discovery, we identify over 1.1 million <i>cis</i>-irQTLs (minor allele frequency [MAF] ≥ 0.01, ±1 Mb of 10,883 isoform transcripts, <i>P</i> &lt; 5 × 10<sup>−8</sup>) across 4,971 genes. Among 11,425 sentinel <i>cis</i>-irQTLs, 72% replicate (<i>P</i> &lt; 1 × 10<sup>−4</sup>) in the Women’s Health Initiative (WHI; <i>n</i> = 2005). Notably, 20% of <i>cis</i>-irQTLs have no significant association with overall gene expression, indicating isoform-specific regulation. These variants are enriched at splice donor/acceptor sites and genome-wide association study loci (<i>P</i> &lt; 1 × 10<sup>−10</sup>). We also identify 1870 sentinel <i>trans</i>-irQTLs (MAF ≥ 0.01, <i>P</i> &lt; 1.5 × 10<sup>−13</sup>) for 1,084 isoforms across 590 genes, and 2327 rare <i>cis</i>-irQTLs (0.003 &lt; MAF &lt; 0.01) for 2467 isoforms of 1428 genes in FHS, with external replication rates of 61% and 41% in WHI, respectively. We highlight rs12898397 in <i>ULK3</i>, which alters splice site usage and reduces expression of a full-length isoform. Mendelian randomization supports a causal role between this isoform shift and reduced diastolic blood pressure. These findings highlight the power of irQTL mapping to uncover transcript-specific regulatory mechanisms underlying complex traits.</p>

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Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月22日

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  • Chunyu Liu,
  • Roby Joehanes,
  • Jiantao Ma,
  • Jiuyong Xie,
  • Jian Yang,
  • Mengyao Wang,
  • Tianxiao Huan,
  • Shih-Jen Hwang,
  • Jia Wen,
  • Quan Sun,
  • Cumhur Y. Demirkale,
  • Nancy L. Heard-Costa,
  • Peter Orchard,
  • April P. Carson,
  • Jeffrey W. Haessler,
  • Laura M. Raffield,
  • Alex P. Reiner,
  • Nora Franceschini,
  • Paul L. Auer,
  • Charles Kooperberg,
  • Yun Li,
  • George O’Connor,
  • Joanne M. Murabito,
  • Peter Munson,
  • Daniel Levy

摘要

We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham Heart Study (FHS, n = 2622) discovery, we identify over 1.1 million cis-irQTLs (minor allele frequency [MAF] ≥ 0.01, ±1 Mb of 10,883 isoform transcripts, P < 5 × 10−8) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10−4) in the Women’s Health Initiative (WHI; n = 2005). Notably, 20% of cis-irQTLs have no significant association with overall gene expression, indicating isoform-specific regulation. These variants are enriched at splice donor/acceptor sites and genome-wide association study loci (P < 1 × 10−10). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10−13) for 1,084 isoforms across 590 genes, and 2327 rare cis-irQTLs (0.003 < MAF < 0.01) for 2467 isoforms of 1428 genes in FHS, with external replication rates of 61% and 41% in WHI, respectively. We highlight rs12898397 in ULK3, which alters splice site usage and reduces expression of a full-length isoform. Mendelian randomization supports a causal role between this isoform shift and reduced diastolic blood pressure. These findings highlight the power of irQTL mapping to uncover transcript-specific regulatory mechanisms underlying complex traits.