To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn’s Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10^–5). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10^–5) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10⁻³ and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10^–3, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing.

为了进一步探索复杂性状之间的遗传联系，我们开发了一个全面的框架来协调和整合来自四个特征明确的队列的广泛基因型和表型数据，重点是存储在基因型和表型数据库 (dbGaP) 中的心脏代谢疾病。我们生成了一系列多基因风险评分 (PRS)，以研究赋予 19 种常见疾病和特征对身高、2 型糖尿病 (T2D) 和心肌梗塞 (MI) 的遗传风险的基因座的多效性。在对 20,021 名受试者的荟萃分析中，我们确定了克罗恩病 (CD)（一种炎症性肠病）和身高 ( p  = 5.5 × 10 ^–5 ) 的共同遗传决定因素。PRS-CD 与身高的关联在 UK Biobank ( p = 1.1 × 10 ^-5 ) 和 510 名 CD 病例和对照的独立队列（每 PRS-CD 四分位间距增加 1.57 cm，p  = 5.0 × 10 ^-3和每四分位 PRS-CD 增加的 CD 风险降低 28%高度，p  = 1.1 × 10 ^–3，效果独立于 CD 诊断）。对 PRS-height 和 PRS-CD 之间重叠变异的通路分析检测到炎症、免疫介导和生长因子调节通路的基因显着富集。这一发现支持了儿童期 CD 患者生长障碍的临床观察，并证明了使用来自 dbGaP 的个体水平数据来寻找共享遗传决定因素的价值。这些信息有助于深入了解疾病的发病机制，并可能对新疗法和药物再利用产生重大影响。