Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 136, Issue 3, Pages 593-602Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2015.11.026
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Funding
- Spanish Ministry of Economy and Competitiveness [PSE-010000-2006-6, IPT-010000-2010-36]
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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 casecontrol individuals from Spain. We performed a genomewide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (P-FDR <= 2.55 x 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 (P-FDR <= 3.46 x 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (P-combined = 1.84 x 10(-4)), the transport of inorganic ions and amino acids (P-combined = 1.57 x 10(-7)), and posttranslational protein modification (P-combined = 1.57 x 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional casecontrol cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility.
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