Deep sequencing of 1320 genes reveals the landscape of protein-truncating variants and their contribution to psoriasis in 19,973 Chinese individuals

Abstract

Protein-truncating variants (PTVs) have important impacts on phenotype diversity and disease. However, their population genetics characteristics in more globally diverse populations are not well defined. Here, we describe patterns of PTVs in 1320 genes sequenced in 10,539 healthy controls and 9434 patients with psoriasis, all of Han Chinese ancestry. We identify 8720 PTVs, of which 77% are novel, and estimate 88% of all PTVs are deleterious and subject to purifying selection. Furthermore, we show that individuals with psoriasis have a significantly higher burden of PTVs compared to controls (P = 0.02). Finally, we identified 18 PTVs in 14 genes with unusually high levels of population differentiation, consistent with the action of local adaptation. Our study provides insights into patterns and consequences of PTVs.

COVID-19 severity: does the genetic landscape of rare variants matter?

“…In the elderly group, the association effect was enhanced not only because of the presence of a large number of QVs in severe patients, but also because of a small number of these variants in patients with non-severe COVID-19. Since the burden of rare variants may be associated with chronic diseases ( Ganna et al, 2018 ; Farhan et al, 2019 ; Xu et al, 2021 ; Zoghbi et al, 2021 ) and their severity and younger age of manifestation ( Ganna et al, 2018 ), a genetic landscape with minimal numbers of rare variants may be associated with healthy aging and absence of comorbidities aggravating the course of COVID-19. Regarding comorbid conditions, overrepresentation of rare HI variants was found in all three subgroups of patients with severe COVID-19, with the lowest signal observed in the obese subgroup.…”

“…A significant excess of rare QVs in genes intolerant to loss of function or missense variants was observed in patients with psychiatric disorders ( Ganna et al, 2018 ; Feng et al, 2019 ; Zoghbi et al, 2021 ) and amyotrophic lateral sclerosis ( Farhan et al, 2019 ). A higher burden of QVs in patients with psoriasis compared to controls was found in the immune disease-related gene set ( Xu et al, 2021 ). An enrichment in deleterious ultra-rare variants in gene sets previously associated with epilepsy was observed in epilepsy-affected individuals compared to controls ( Feng et al, 2019 ).…”

Research Progress of Genomic Variation in Psoriasis

“…10 To more fully analyze the genetic deletions of psoriasis in the past few years, researchers have used many new methods to analyze more types of genomic structural variations (SVs), especially those that have a greater impact on protein function, such as small insertions and deletions (InDels), 11 copy number variation (CNV), 12 and protein-truncating variants. 13 These studies complement the lack of genetic descriptions of psoriasis in traditional GWASs and provide more evidence for precision medicine in psoriasis.…”

Structural variations in crocodile lizard populations provide novel insights into genomic variations in endangered animals

“…Notably, almost all of these variants are absence variants, which may have important consequences for gene function. Gene absence variations include not only the complete absence of genes but also the truncation of genes, many of which can still be transcribed, albeit with potentially altered protein function (Xu et al, 2021). Consequently, even though Xie et al, (2022) found that small populations of crocodile lizards can effectively eliminate deleterious variation, it is conceivable that the adverse effects of the accumulation of gene absence variations on the survival of these lizards may still be ongoing.…”