Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn's disease

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.