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

Antonio Di Narzo, Itziar Frades, Heidi M Crane, Paul K Crane, Jean-Sebastian Hulot, Andrew Kasarskis, Amy Hart, Carmen Argmann, Marla Dubinsky, Inga Peter, Ke Hao

Journal: Human genetics 2021;140(6):865-877

PMID: 33452914

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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). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10, 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.

Address: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.; Icahn School of Medicine At Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.; Computational Biology and Systems Biomedicine Research Group, Biodonostia Health Research Institute, San Sebastián, Spain.; Department of Medicine, University of Washington, Seattle, WA, USA.; Center for AIDS Research, University of Washington, Seattle, WA, USA.; Department of Medicine, University of Washington, Seattle, WA, USA.; Université de Paris, INSERM, PARCC, CIC1418, F-75015, Paris, France.; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.; Icahn School of Medicine At Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, NY, USA.; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Janssen R&D, LLC, 1400 McKean Road, Spring House, PA, USA.; Department of Pediatric Gastroenterology and Nutrition, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA. [email protected].; Icahn School of Medicine At Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, NY, USA. [email protected].

DOI: 10.1007/s00439-020-02250-3