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

Abstract

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.

Figure 1.. Study Design.

dbGAP, database of Genotypes and Phenotypes; T2D, type 2 diabetes; MI, myocardial infarction; GWAS, genome-wide association study; IBD, inflammatory bowel disease; EduYear, years of education.

Figure 2.. Associations of polygenic risk scores (PRS) for 19 traits constructed using various GWAS p-value thresholds with type 2 diabetes (T2D), myocardial infarction (MI), and body height.

A. Z scores of association between polygenic scores and height for different genetically determined traits (vertical axis) computed at different GWAS p-value cutoffs (horizontal axis). Associations with nominal p < 0.001 are marked with a black dot. B. Forest plot of association coefficients (β in cm, x-axis) between PRS for Crohn’s disease (CD, p-value threshold ≤ 1E-3) and observed body height in the discovery and replication cohorts. ARIC, the Atherosclerosis Risk in Communities Study; Framingham, the Framingham Heart Study; CARDIA, the Coronary Artery Risk Development in Young Adults Study; MESA, the Multi-Ethnic Study of Atherosclerosis; MSCCR, Mount Sinai Crohn’s and Colitis Registry; UKBB, UK Biobank.

Figure 3.. Intersection between Crohn’s disease and height-associated variants in the respective polygenic risk scores and their enrichment in biological pathways.

A. Number of overlapping variants for Crohn’s disease (CD) and height at GWAS p ≤ 0.001; B. Top enriched biological process networks by MetaCore (Thomson Reuters); C. Gene-set enrichment analysis (GSEA) using Biocarta in Molecular Signatures Database, MSigDB.

Figure 4.. Summary of genes intersecting between polygenic risk scores for immune-mediated diseases and adult height.

RA, rheumatoid arthritis; UC, ulcerative colitis; CD, Crohn’s disease.