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

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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 × 10–5). 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 overlap** 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.

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Data availability

Database of Genotypes and Phenotypes (dbGaP, https://www.ncbi.nlm.nih.gov/gap). MetaCore (Thomson Reuters; https://portal.genego.com). Molecular Signatures Database, MSigDB (http://software.broadinstitute.org/gsea/msigdb).

Code availability

The code is available upon request.

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Funding

This work was supported by the National Heart, Lung, And Blood Institute [R01HL125027 to IP and HMC], National Human Genome Research Institute [R01HG010649 to IP and HMC], National Institute on Drug Abuse [R01DA047045 to HMC and IP], National Institute of Diabetes and Digestive and Kidney [U24DK062429 and R01DK106593 to KH], National Institute of Environmental Health Sciences [R01ES029212 to KH]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA

    Antonio Di Narzo, Itziar Frades, Andrew Kasarskis, Carmen Argmann, Inga Peter & Ke Hao

  2. Icahn School of Medicine At Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, NY, USA

    Antonio Di Narzo, Andrew Kasarskis, Carmen Argmann, Inga Peter & Ke Hao

  3. Computational Biology and Systems Biomedicine Research Group, Biodonostia Health Research Institute, San Sebastián, Spain

    Itziar Frades

  4. Department of Medicine, University of Washington, Seattle, WA, USA

    Heidi M. Crane & Paul K. Crane

  5. Center for AIDS Research, University of Washington, Seattle, WA, USA

    Heidi M. Crane

  6. Université de Paris, INSERM, PARCC, CIC1418, F-75015, Paris, France

    Jean-Sebastian Hulot

  7. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jean-Sebastian Hulot

  8. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Andrew Kasarskis

  9. Janssen R&D, LLC, 1400 McKean Road, Spring House, PA, USA

    Amy Hart

  10. Department of Pediatric Gastroenterology and Nutrition, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Marla Dubinsky

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  1. Antonio Di Narzo
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  2. Itziar Frades
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  11. Ke Hao
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Contributions

KH, IP—conceptualization. KH, IP, IF, HMC, PKC, JSH—data curation. KH, IP, IF, HMC, PKC, JSH, MD—investigation. ADN, KH—methodology and formal analysis. AK, AH, CA—validation and resources. IP, KH, MD—supervision. ADN, IP, KH—original draft preparation. IF, HMC, PKC, JSH, AK, AH, CA, MD—review and editing.

Corresponding author

Correspondence to Ke Hao.

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The authors declare no competing interests.

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The study was approved by the Icahn School of Medicine Institutional Review Board.

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Study participants for the Mount Sinai Crohn’s and Colitis Registry were consented using a written informed consent.

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Di Narzo, A., Frades, I., Crane, H.M. et al. Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn’s disease. Hum Genet 140, 865–877 (2021). https://doi.org/10.1007/s00439-020-02250-3

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