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<p>Genome-wide association studies have predominantly implicated common variants in lung cancer susceptibility, whereas the contribution of rare non-coding variation remains incompletely defined. This study comprised 52,550 cases and 1,617,173 controls across three whole-genome sequencing (WGS) cohorts (UK Biobank, the 100,000 Genomes Project, and All of Us) and five imputed genotype-array datasets aimed to identify rare non-coding determinants of lung cancer risk. Two complementary approaches were applied: position-based single-variant testing for variants with adequate allele counts, and gene-based testing aggregating rare and ultra-rare ncRNA variants to increase power. Single-variant meta-analysis identified two novel rare non-coding variants reaching sequencing-based genome-wide significance: rs763076863<sub><i>C22orf46</i></sub> at 22q13.2 [OR (95% CI): 5.94 (3.46–10.19), <i>P</i> = 4.55 × 10<sup>-9</sup>] and rs1014871851<sub><i>WWOX</i></sub> at 16q23.1 [OR (95% CI): 7.55 (4.50–12.67), <i>P</i> = 3.71 × 10<sup>-9</sup>]. Functional annotation–informed gene-based analyses prioritized 37 candidate ncRNAs using eQTL, expression, proteomics, prognosis, <i>cis</i>-Mendelian randomization drug-target evidence, and external replication. <i>CLEC12A-AS1</i> ranked highest; multi-omics association and chain mediation analyses supported an indirect pathway linking <i>CLEC12A-AS1</i> burden to lung cancer risk via modulation of <i>CLEC12A</i>. Collectively, results indicate contributions from both individually detectable rare variants and cumulative ultra-rare functional burden within ncRNA regions, highlighting the <i>CLEC12A-AS1</i>/<i>CLEC12A</i> axis as a potential biomarker and translational target.</p>

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Genetic architecture of lung cancer revealed by common and rare variant analyses across population-scale biobanks

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月13日

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  • Jingyi Zhao,
  • Lei Qiao,
  • Yixin Zhang,
  • Hao Hong,
  • Qinhui Fan,
  • David C. Christiani,
  • Feng Chen,
  • Yang Zhao,
  • Sipeng Shen

摘要

Genome-wide association studies have predominantly implicated common variants in lung cancer susceptibility, whereas the contribution of rare non-coding variation remains incompletely defined. This study comprised 52,550 cases and 1,617,173 controls across three whole-genome sequencing (WGS) cohorts (UK Biobank, the 100,000 Genomes Project, and All of Us) and five imputed genotype-array datasets aimed to identify rare non-coding determinants of lung cancer risk. Two complementary approaches were applied: position-based single-variant testing for variants with adequate allele counts, and gene-based testing aggregating rare and ultra-rare ncRNA variants to increase power. Single-variant meta-analysis identified two novel rare non-coding variants reaching sequencing-based genome-wide significance: rs763076863C22orf46 at 22q13.2 [OR (95% CI): 5.94 (3.46–10.19), P = 4.55 × 10-9] and rs1014871851WWOX at 16q23.1 [OR (95% CI): 7.55 (4.50–12.67), P = 3.71 × 10-9]. Functional annotation–informed gene-based analyses prioritized 37 candidate ncRNAs using eQTL, expression, proteomics, prognosis, cis-Mendelian randomization drug-target evidence, and external replication. CLEC12A-AS1 ranked highest; multi-omics association and chain mediation analyses supported an indirect pathway linking CLEC12A-AS1 burden to lung cancer risk via modulation of CLEC12A. Collectively, results indicate contributions from both individually detectable rare variants and cumulative ultra-rare functional burden within ncRNA regions, highlighting the CLEC12A-AS1/CLEC12A axis as a potential biomarker and translational target.