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

Hum Genet. 2021 Jun;140(6):865-877. doi: 10.1007/s00439-020-02250-3. Epub 2021 Jan 16.

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.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Body Height / genetics*
  • Body Height / immunology
  • Child
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Crohn Disease / pathology
  • Databases, Genetic
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / immunology
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Humans
  • Immune Checkpoint Proteins / genetics
  • Immune Checkpoint Proteins / immunology
  • Immunity, Innate
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / immunology
  • Male
  • Multifactorial Inheritance / immunology
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / immunology
  • Myocardial Infarction / pathology
  • Phenotype
  • Risk Factors

Substances

  • Immune Checkpoint Proteins
  • Intercellular Signaling Peptides and Proteins