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Background: The genetic association of allergic rhinitis (AR) with other physiological systems throughout the human body remains unknown. Objective: The aim of this Mendelian randomization (MR) study was to explore the association of this respiratory disorder with multiple common sleep and neuropsychological disorders at the genetic level. Methods: Summary data for total AR and pollen AR were collected from the most updated FinnGen genome-wide association studies involving more than 340 000 European subjects. Summary data for 12 sleep and neuropsychological disorders (including snoring) were included from UK Biobank studies involving 63 392 to 462 933 European subjects. Three MR methods, including inverse-variance weighting (IVW), weighted median and MR–Egger, were used to determine the relationships between the exposures and outcomes. Several sensitivity analyses, including Cochran's Q, MR–Egger intercept, MR-PRESSO, "leave-one-out" test and funnel plot, were used to detect heterogeneity and horizontal pleiotropy. Results: IVW revealed that total and pollen AR were associated with an increased risk of snoring (odds ratio (OR) = 1.011, 95% confidence interval (CI) = 1.004∼1.019, P =.003; OR = 1.006, 95% CI = 1.001∼1.011, P =.014). Two other MR methods supported the results from the IVW analysis. No heterogeneity or horizontal pleiotropy was confirmed by sensitivity analyses. In addition, IVW did not reveal any association between AR and other included disorders. Conclusion: AR (specifically AR caused by pollen) might be an independent risk factor for snoring at the genetic level, which should be verified in the future. [ABSTRACT FROM AUTHOR]

Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported. Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls). We identified 6 genome-wide significant (P < 5 × 10–8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10–19) was a missense variant (p.Cys712Phe) in the LGR5 gene , a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling. Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5 , a canonical marker of adult intestinal stem cells. Missense variant in LGR5, a canonical intestinal stem cell marker associates with small intestinal-neuroendocrine tumor risk. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. We completed a genome-wide meta-analysis of AD in 796,661 individuals (N cases = 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. We report 30 loci associating with AD (P < 5 × 10−8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future. [ABSTRACT FROM AUTHOR]