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Background <p>While it is commonly observed that congenital malformations (CM), birth weight and neuroblastoma (NB) often co-occur clinically, there is a scarcity of studies investigating their relationship.</p> Aim <p>To investigate the causal relationship between CM, birth weight and NB using two-sample mendelian randomization (MR) analysis.</p> Methods <p>This study utilized data from the Genome-Wide Association Studies (GWAS) database for CM, birth weight, and NB. We identified and analyzed single nucleotide polymorphisms (SNPs) related to CM from various organ systems, ensuring robust instrumental variables through linkage disequilibrium (LD) and F-statistic testing. SNPs were further validated in GWAS Catalog to exclude weak variables. We employed various MR methods including inverse variance weighted (IVW), MR-Egger regression, weighted median, simple mode and weighted mode to assess the causal relationships. Sensitivity analyses were performed using leave-one-out (LOO) and MR-PRESSO.</p> Results <p>The analysis demonstrated a protective effect of genital organ CM, which were inversely associated with both overall neuroblastoma (OR = 0.71, 95% CI: 0.60–0.85, <i>P</i> = 0.001) and the 11q-deleted subtype (OR = 0.33, 95% CI: 0.13–0.85, <i>P</i> = 0.02). In contrast, urinary system,gallbladder, bile ducts, and liver were positively associated with neuroblastoma harbouring 11q deletion (OR = 2.37, 95% CI: 1.32–4.27, <i>P</i> = 0.01),(OR = 1.47, 95% CI: 1.17–1.84 <i>P</i> = 0.001) but not with NB overall.However, no significant associations were found between other CM types, birth weight, and NB, and no evidence of heterogeneity, horizontal pleiotropy, or outlier SNPs was identified.</p> Conclusion <p>Genital organ malformations confer protection against both overall and 11q-deleted neuroblastoma, whereas urinary system, gallbladder, biliary and liver malformations increase risk exclusively for 11q-deleted disease. However, due to the relaxed p-value threshold used for instrument selection, these findings should be interpreted cautiously and warrant replication with stricter criteria.</p>

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Causal links between congenital malformations, birth weight, and neuroblastoma: insights from Mendelian randomization

  • 期刊论文

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  • 发表日期：

    2025年11月14日

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  • Ailikamu Aierken,
  • Falide Atabieke,
  • Yierzhati Aizezi,
  • Munire Aierken,
  • Shui-Xue Li,
  • Ling Zhou

摘要

Background

While it is commonly observed that congenital malformations (CM), birth weight and neuroblastoma (NB) often co-occur clinically, there is a scarcity of studies investigating their relationship.

Aim

To investigate the causal relationship between CM, birth weight and NB using two-sample mendelian randomization (MR) analysis.

Methods

This study utilized data from the Genome-Wide Association Studies (GWAS) database for CM, birth weight, and NB. We identified and analyzed single nucleotide polymorphisms (SNPs) related to CM from various organ systems, ensuring robust instrumental variables through linkage disequilibrium (LD) and F-statistic testing. SNPs were further validated in GWAS Catalog to exclude weak variables. We employed various MR methods including inverse variance weighted (IVW), MR-Egger regression, weighted median, simple mode and weighted mode to assess the causal relationships. Sensitivity analyses were performed using leave-one-out (LOO) and MR-PRESSO.

Results

The analysis demonstrated a protective effect of genital organ CM, which were inversely associated with both overall neuroblastoma (OR = 0.71, 95% CI: 0.60–0.85, P = 0.001) and the 11q-deleted subtype (OR = 0.33, 95% CI: 0.13–0.85, P = 0.02). In contrast, urinary system,gallbladder, bile ducts, and liver were positively associated with neuroblastoma harbouring 11q deletion (OR = 2.37, 95% CI: 1.32–4.27, P = 0.01),(OR = 1.47, 95% CI: 1.17–1.84 P = 0.001) but not with NB overall.However, no significant associations were found between other CM types, birth weight, and NB, and no evidence of heterogeneity, horizontal pleiotropy, or outlier SNPs was identified.

Conclusion

Genital organ malformations confer protection against both overall and 11q-deleted neuroblastoma, whereas urinary system, gallbladder, biliary and liver malformations increase risk exclusively for 11q-deleted disease. However, due to the relaxed p-value threshold used for instrument selection, these findings should be interpreted cautiously and warrant replication with stricter criteria.