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.

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus

“…The genome-wide pathway analysis (GWPA) has been recently used to characterize the genetic basis of several complex diseases like cancer [19]. Very recently, using the GWPA approach we have identified new genetic variation associated with psoriasis, an autoimmune disease of the skin [20]. This result confirms the utility of GWPA in the study of the genetics of autoimmune diseases.…”

“…In the present study, the GWPA was performed using the set-based test implemented in the PLINK software as described previously [20, 23]. Compared to other methods, this set-based test uses genotype data to estimate pathway association instead of P values for significance.…”

Depletion of Saccharomyces cerevisiae in psoriasis patients, restored by Dimethylfumarate therapy (DMF)

“…cerevisiae abundance, suggesting that genetic variants affecting immune cell function can modulate microbial abundance [5]. However, to the best of our knowledge, the CARD9 IBD-risk allele has so far not been associated with psoriasis [19, 20]. Furthermore, while SNPs in other immunity genes may potentially contribute to an altered microbial balance, it is important to note that such disease-associated alleles, while more prevalent in disease, are also present in healthy individuals, and are therefore unlikely to (solely) explain the decreased S .…”

Leveraging Molecular Data Analysis to Understand Drug Response in Systemic Sclerosis

“…However, this approach does not incorporate previous knowledge into the analysis. One way of leveraging this process begins with the analysis of genes in functionally related groups or pathways (Aterido et al, 2016;Subramanian et al, 2005) (Figure 1). This approach has become increasingly popular because it reduces the complexity of the analysis (thousands of genes to hundreds of pathways) and it provides more readily interpretable results.…”