Three novel structural variations at the major histocompatibility complex and IL12B predispose to psoriasis

Background Structural variations (SVs; defined as DNA variants >= 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. Objectives To investigate the association of SVs and psoriasis. Methods Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population. Fine-mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. Results In total, we obtained 4535 SVs and identified two novel deletions [esv3608550, odds ratio (OR) 2 center dot 73 (P < 2 center dot 00 x 10(-308)); esv3608542, OR 0 center dot 47 (P = 7 center dot 40 x 10(-28))] at 6q21 center dot 33 (major histocompatibility complex), one novel Alu element insertion [esv3607339; OR 1 center dot 22 (P = 1 center dot 18 x 10(-35))] at 5q33 center dot 3 (IL12B) and confirmed one previously reported deletion [esv3587563; OR 1 center dot 30 (P = 9 center dot 52 x 10(-60))] at 1q21 center dot 2 (late cornified envelope) for psoriasis. Fine-mapping analysis including single-nucleotide polymorphisms (SNPs) and small insertions/deletions revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP [rs9378188; OR, 1 center dot 65 (P = 3 center dot 46 x 10(-38))] was identified at 6q21 center dot 33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of two deletions at 6q21 center dot 33 with psoriasis might relate to their influence on the expression of HLA-C. Conclusions We have constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis, and highlight the non-negligible impact of SVs on complex diseases.