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 x 10(-5)). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 x 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 x 10(-3) and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 x 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.

Automated summary

The study identified shared genetic determinants between Crohn's Disease (CD) and height, shedding light on the pathogenesis of the disease. This research demonstrates the value of using individual-level data from dbGaP in exploring shared genetic factors and could potentially impact novel therapies and drug repurposing.