title: Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry.
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.
authors.affiliation: Department of Biostatistics, Harvard University, Cambridge, MA, USA.|Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lareau
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: DeWeese
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: I
authors.initials: I
authors.lastname: Adrianto
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.|Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lessard
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Department of Medicine, Staten Island University Hospital, Staten Island, NY, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Iannuzzi
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Rybicki
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.|Center for Bioinformatics, Henry Ford Health System, Detroit, MI, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Levin
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Montgomery
mesh_terms: D001741:Black or African American / Q000235:genetics; D058685:Genetic Pleiotropy; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D020412:Multifactorial Inheritance; D012507:Sarcoidosis / Q000235:genetics* / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D007378:Interleukins; C464565:MYDGF protein, human; D018664:Interleukin-12