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

• Published in: Human genetics Vol. 140; no. 6; pp. 865 - 877
• Main Authors: Di Narzo, Antonio, Frades, Itziar, Crane, Heidi M., Crane, Paul K., Hulot, Jean-Sebastian, Kasarskis, Andrew, Hart, Amy, Argmann, Carmen, Dubinsky, Marla, Peter, Inga, Hao, Ke
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2021; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adult; Analysis; Biomedical and Life Sciences; Biomedicine; Body height; Body Height - genetics; Body Height - immunology; Child; Children; Crohn Disease - genetics; Crohn Disease - immunology; Crohn Disease - pathology; Crohn's disease; Databases, Genetic; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - immunology; Diabetes Mellitus, Type 2 - pathology; Disease; Female; Gastrointestinal diseases; Gene Expression Regulation; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genotypes; Health risk assessment; Heart attack; Human Genetics; Humans; Immune Checkpoint Proteins - genetics; Immune Checkpoint Proteins - immunology; Immunity, Innate; Inflammatory bowel diseases; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Intestine; Life Sciences; Male; Mediation; Meta-analysis; Metabolic Diseases; Molecular Medicine; Multifactorial Inheritance - immunology; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - immunology; Myocardial Infarction - pathology; Original Investigation; Phenotype; Phenotypes; Polygenic inheritance; Risk Factors; Type 2 diabetes
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-020-02250-3

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.