title: Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.
abstract: Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility.
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Adrià
authors.initials: A
authors.lastname: Aterido
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain. Electronic address: toni.julia@vhir.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julià
authors.affiliation: Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrándiz
authors.affiliation: Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Puig
authors.affiliation: Dermatology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fonseca
authors.affiliation: Dermatology Department, Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Fernández-López
authors.affiliation: Dermatology Department, Hospital Universitario La Princesa, Madrid, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Dauden
authors.affiliation: Dermatology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: José Luís
authors.initials: JL
authors.lastname: Sánchez-Carazo
authors.affiliation: Dermatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain.
authors.forename: José Luís
authors.initials: JL
authors.lastname: López-Estebaranz
authors.affiliation: Dermatology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Moreno-Ramírez
authors.affiliation: Dermatology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vanaclocha
authors.affiliation: Dermatology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Herrera
authors.affiliation: Dermatology Department, Hospital Universitario Infanta Leonor, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: de la Cueva
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Dand
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Palau
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Arnald
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López-Lasanta
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Raül
authors.initials: R
authors.lastname: Tortosa
authors.affiliation: Spanish National DNA Bank, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: García-Montero
authors.affiliation: Life Sciences, Barcelona Supercomputing Centre, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Codó
authors.affiliation: Life Sciences, Barcelona Supercomputing Centre, Barcelona, Spain.
authors.forename: Josep Lluís
authors.initials: JL
authors.lastname: Gelpí
authors.affiliation: Spanish National Genotyping Centre (CeGen), Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Bertranpetit
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK; St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain. Electronic address: sara.marsal@vhir.org.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011565:Psoriasis / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D012016:Reference Values; D018570:Risk Assessment; D013030:Spain / Q000453:epidemiology