Open AccessMeta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn’s disease
Author(s) -
Antonio Di Narzo,
Itziar Frades,
Heidi M. Crane,
Paul K. Crane,
JeanSébastien Hulot,
Andrew Kasarskis,
Amy Hart,
Carmen Argmann,
Marla Dubinsky,
Inga Peter,
Ke Hao
Publication year - 2021
Publication title -
human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.351
H-Index - 137
eISSN - 1432-1203
pISSN - 0340-6717
DOI - 10.1007/s00439-020-02250-3
Subject(s) - biology , disease , interquartile range , genome wide association study , human genetics , crohn's disease , genetics , genotype , phenotype , bioinformatics , medicine , gene , single nucleotide polymorphism
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.