Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

TitleGenome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.
Publication TypeJournal Article
Year of Publication2016
AuthorsAterido, Adrià, Julià Antonio, Ferrándiz Carlos, Puig Lluís, Fonseca Eduardo, Fernández-López Emilia, Dauden Esteban, Sánchez-Carazo José Luís, López-Estebaranz José Luís, Moreno-Ramírez David, Vanaclocha Francisco, Herrera Enrique, de la Cueva Pablo, Dand Nick, Palau Nuria, Alonso Arnald, López-Lasanta María, Tortosa Raül, García-Montero Andrés, Codó Laia, Gelpí Josep-Lluis, Bertranpetit Jaume, Absher Devin, Capon Francesca, Myers Richard M., Barker Jonathan N., and Marsal Sara
JournalJ Invest Dermatol
Date Published2016 Mar
KeywordsAdult, Case-Control Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Prevalence, Psoriasis, Reference Values, Risk Assessment, Single Nucleotide, Spain

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.

Alternate JournalJ. Invest. Dermatol.