Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis

Abstract

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture. We hypothesized that there are shared genetic components between psoriasis and T2D. Trans-disease meta-analysis was applied to 8,016,731 well-imputed genetic markers from large-scale meta-analyses of psoriasis (11,024 cases and 16,336 controls) and T2D (74,124 cases and 824,006 controls), adjusted for body mass index. We confirmed our findings in a hospital-based study (42,112 patients) and tested for causal relationships with multivariable Mendelian randomization. Mendelian randomization identified a causal relationship between psoriasis and T2D (P = 1.6 × 10^‒4, OR = 1.01) and highlighted the impact of body mass index. Trans-disease meta-analysis further revealed four genome-wide significant loci (P < 5 × 10^‒8) with evidence of colocalization and shared directions of effect between psoriasis and T2D not present in body mass index. The proteins coded by genes in these loci (ACTR2, ERLIN1, TRMT112, and BECN1) are connected through NF-κB signaling. Our results provide insight into the immunological components that connect immune-mediated skin conditions and metabolic diseases, independent of confounding factors.

Figure 1:. Trans-disease Meta-analysis.

a) Vertical Manhattan plots of the meta-analysis association results for psoriasis and T2D, showing genome-wide significant (p≤5x10⁻⁸) markers in red and shared loci identified by our trans-disease meta-analysis in blue. b) Regional association plots for the chromosome 10 locus in psoriasis and T2D (with the lead marker in purple). The locus is suggestive significant for each disease and genome-wide significant in the trans-disease meta-analysis.

Figure 2:. Cell Type Enrichment for Trans-Disease Meta-Analysis Markers Outside the MHC.

a) Calculated using DNAse hotspots in GARFIELD. b) Using H3K27ac marks from Farh et al.(Farh et al., 2015) The enrichment results illustrate immune-cell involvement.