Psoriasis and other complex trait dermatoses: from Loci to functional pathways

Abstract

Driven by advances in molecular genetic technologies and statistical analysis methodologies, there have been huge strides taken in dissecting the complex genetic basis of many inflammatory dermatoses. One example is psoriasis, for which application of classical linkage analysis and genome-wide association investigation has identified genetic loci of major and minor effect. Although most loci independently have modest genetic effects, they identify important biological pathways potentially relevant to disease pathogenesis and therapeutic intervention. In the case of psoriasis, these appear to involve the epidermal barrier, NF-κB mechanisms, and T helper type 17 adaptive immune responses. The advent of next-generation sequencing methods will permit a more detailed and complete map of disease genetic architecture, a key step in developing personalized medicine strategies in the clinical management of the complex inflammatory dermatoses.

Figure 1

An example of a Manhattan plot summarising the association results generated by a GWAS. SNPs are plotted according to their chromosomal location and each dot represents the P value (plotted as −log₁₀ P) associated with a single marker. Green dots refer to susceptibility regions that were known at the onset of the study, with the PSORS1 signal (which generated a P < 10⁻²⁰⁰, but is cut here at P = 10⁻¹⁰) on chromosome 6 dominating the genetic landscape. Red dots highlight novel susceptibility loci. Reproduced from Strange et al, Nat Genet 2010 42:985-90.

Figure 2

Genetic studies suggest an integrated model for the pathogenesis of psoriasis. Alterations in skin barrier and immune genes determine abnormal responses to external agents (e.g. viruses detected by IFIH1), resulting in chronic skin inflammation.