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Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry

Genes & Immunity volume 18, pages 88–94 (2017)Cite this article

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Abstract

Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R2=2.03%; P=8.89 × 10−9), celiac disease (R2=2.03%; P=8.21 × 10−9), primary biliary cirrhosis (R2=2.43%; P=2.01 × 10−10) and rheumatoid arthritis (R2=4.32%; P=2.50 × 10−17). These associations validate in African Americans only after accounting for the proportion of genome-wide European ancestry, where we demonstrate similar effects of polygenic risk for African-Americans with the highest levels of European ancestry. Variants and genes implicated in European-American pleiotropic associations were enriched for pathways involving interleukin-12, interleukin-27 and cell adhesion molecules, corroborating the hypothesized immunopathogenesis of disease.

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Acknowledgements

We thank the OMRF Genomics core for performing the genotyping experiments and the useful discussion. We are also grateful to the EVE asthma analysis consortium (RC2 HL101651) and particularly the efforts of Drs Carole Ober, Dan Nicolae and Dara Torgerson to make the asthma summary statistics available to the broader scientific community. Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS), Heart, Lung and Blood Institute (NHLBI), and National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers: P20GM103456 and P30GM110766 to IA, R01-HL54306 and U01-HL060263 to MCI, R56-AI072727 and R01-HL092576 to BAR, and P30 GM110766-01, RC2HL101499 and R01HL113326 to CGM. CAL is supported by an NSF Graduate Research Fellowship # DGE1144152. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

Conceived and designed the study: CAL, CFD, MCI, BAR, AML and CGM. Analyzed data: CAL, CFD, IA and AML. Interpreted the data, drafted/revised the manuscript: CAL, CFD, IA, CJL, PMG, MCI, BAR, AML and CGM.

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Authors and Affiliations

  1. Department of Biostatistics, Harvard University, Cambridge, MA, USA

    C A Lareau

  2. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    C A Lareau, C F DeWeese, I Adrianto, C J Lessard, P M Gaffney & C G Montgomery

  3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    C J Lessard

  4. Department of Medicine, Staten Island University Hospital, Staten Island, NY, USA

    M C Iannuzzi

  5. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

    B A Rybicki & A M Levin

  6. Center for Bioinformatics, Henry Ford Health System, Detroit, MI, USA

    A M Levin

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  1. C A Lareau
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Correspondence to C G Montgomery.

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Lareau, C., DeWeese, C., Adrianto, I. et al. Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry. Genes Immun 18, 88–94 (2017). https://doi.org/10.1038/gene.2017.3

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