Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is a sudden onset, unexplained sensorineural hearing loss. Depression is a common mental disorder and a leading cause of disability. Here, We used a two-sample Mendelian randomization approach using pooled statistics from genome-wide association studies of ISSHL (1491 cases, 196,592 controls) and depression (23,424 cases, 192,220 controls) in European populations. This study investigated the bidirectional relationship between single nucleotide polymorphisms associated with depression and ISSHL using inverse variance weighting.Additional sensitivity analyses, such as Mendelian randomization-Egger (MR-Egger), weighted median estimates, and leave-one-out analysis, were performed to assess the reliability of the findings. Significant causal association between genetic susceptibility to ISSHL and depression in a random-effects IVW approach (OR = 1.037, 95% CI = 1.004-1.072, P = 0.030). In contrast, genetic depression was not risk factors for ISSHL (OR = 1.134, 95% CI = 0.871-1.475, P = 0.350). After validation by different MR methods and the sensitivity analysis, all of the above results are consistent. The evidence we have gathered suggests a causal relationship between ISSHL and depression. The presence of the former induces or further exacerbates the latter, whereas a similar situation does not exist when the latter is an influencing factor.

UNASSIGNED: Stent thrombosis (ST) is a rare, yet devastating, complication following percutaneous coronary intervention (PCI), with poorly understood pathophysiologic characteristics and genetic backgrounds.
UNASSIGNED: The authors performed a genome-wide association study to identify the common genetic loci associated with early stent thrombosis (EST) and late/very late ST (LST/VLST) in a contemporary Japanese multicenter PCI registry.
UNASSIGNED: Among 8,642 PCI patients included in the registry, 42 who experienced stent thrombosis [EST (n = 15) and LST/VLST (n = 27)] were included (mean age, 67.6 ± 10.8 years; and 88.1% men). We conducted a genome-wide association study using the BioBank Japan patient population as the control (control #1: acute coronary syndrome [n = 29,542] and control #2: effort angina [n = 8,900]) to identify significant single nucleotide polymorphisms (SNPs) and evaluate the performance of polygenic risk scores (PRSs) for predicting these conditions.
UNASSIGNED: We compared patients with EST with controls #1 and #2 and identified SNPs (rs565401593 and rs561634568) in NSD1, and patients with LST/VLST with controls #1 and #2 and identified SNPs (rs532623294 and rs199546342) in GRIN2A. PRS for LST/VLST showed high predictive performance (area under the curve 0.83 [95% CI: 0.76-0.89] and 0.83 [95% CI: 0.77-0.89]), whereas PRS for EST showed modest predictive performance (area under the curve 0.71 [95% CI: 0.58-0.85] and 0.72 [95% CI: 0.58-0.85]).
UNASSIGNED: We identified different genetic predispositions between EST and LST/VLST and demonstrated that the incorporation of PRS may aid in risk prediction of this highly fatal event.

UNASSIGNED: Heart failure (HF) is a disease with numerous genetic and environmental factors that affect it. The results of previous studies indicated that immune phenotypes are associated with HF, but there have been inconclusive studies regarding a causal relationship. Therefore, Mendelian randomization (MR) analyses were undertaken to confirm the causal connections between immune phenotypes and HF, providing genetic evidence supporting the association of immune cell factors with HF risk.
UNASSIGNED: We selected instrumental variables that met the criteria based on data from the results of genome-wide association studies (GWAS) of immune phenotype and all-cause HF. An evaluation of the causal association between 731 immune cell factors and HF risk was carried out using the inverse variance weighted (IVW), MR-Egger regression (MR-Egger), and weighted median (WM) analysis methods. To determine the horizontal pleiotropy, heterogeneity, and stability of the genetic variants, the MR-Egger intercept test, Cochran\'s Q test, MR-PRESSO, and leave-one-out sensitivity analysis were performed.
UNASSIGNED: MR principal method (IVW) analysis showed that a total of 38 immune cell-related factors were significantly causally associated with HF. Further analyses combining three methods (IVW, MR-Egger and WME) showed that six exposure factors significantly associated with heart failure, as shown below. The effect of Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell on heart failure was positive. Whereas, a reverse effect was observed for CD14+ CD16+ monocyte% monocyte.
UNASSIGNED: We investigated the causal relationship between immune phenotypes and all-cause HF. According to the results, Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell aggravate HF, and the risk of HF is decreased by CD14+ CD16+ monocyte% monocyte. These phenotypes may serve as new biomarkers, providing new therapeutic insights for the prevention and treatment of all-cause HF.

BACKGROUND: While genomic variations can provide valuable information for health care and ancestry, the privacy of individual genomic data must be protected. Thus, a secure environment is desirable for a human DNA database such that the total data are queryable but not directly accessible to involved parties (eg, data hosts and hospitals) and that the query results are learned only by the user or authorized party.
OBJECTIVE: In this study, we provide efficient and secure computations on panels of single nucleotide polymorphisms (SNPs) from genomic sequences as computed under the following set operations: union, intersection, set difference, and symmetric difference.
METHODS: Using these operations, we can compute similarity metrics, such as the Jaccard similarity, which could allow querying a DNA database to find the same person and genetic relatives securely. We analyzed various security paradigms and show metrics for the protocols under several security assumptions, such as semihonest, malicious with honest majority, and malicious with a malicious majority.
RESULTS: We show that our methods can be used practically on realistically sized data. Specifically, we can compute the Jaccard similarity of two genomes when considering sets of SNPs, each with 400,000 SNPs, in 2.16 seconds with the assumption of a malicious adversary in an honest majority and 0.36 seconds under a semihonest model.
CONCLUSIONS: Our methods may help adopt trusted environments for hosting individual genomic data with end-to-end data security.

UNASSIGNED: Previous studies have shown interindividual variation in free thyroxine (FT4) serum levels and thyroid stimulating hormone (TSH) in healthy persons. Genetic factors mainly determine this variation, and genome-wide association studies have increased the number of thyroid function-associated variants. The present study investigates the association of candidate variants with FT4 and TSH in a euthyroid Iranian population.
UNASSIGNED: A total of 2931 unrelated euthyroid subjects (FT4 10.29-21.88 pmol/L; TSH 0.32-10 mIU/L, thyroid peroxidase antibody TPOAb < 33 IU/mL in men and < 35 IU/mL in women), with available genotypes were chosen from the Tehran Thyroid Study (TTS), to examine the impact of selected SNPs on thyroid hormone under the additive genetic model. In order to evaluate regional associations with FT4 and TSH levels, a haplotype analysis was done.
UNASSIGNED: We identified a strong association between the rs4338740-C allele and TSH in the adjusted model (β = -0.095, P-value = 0.0004). Also, findings indicated that rs4954192 ACMSD and rs4445669 CADM1 correlated with normal TSH levels (P-value = 0.011, P-value = 0.014, respectively). Haplotype analysis revealed that two haplotypes were significantly associated with TSH levels in euthyroid individuals. The ACGA and AC haplotypes on chromosomes 8 and 14 were significantly correlated with normal TSH levels, respectively (P-value = 0.014, P-value = 0.016).
UNASSIGNED: This is the first genetic association study with TSH and FT4 reference values in an Iranian population. Our findings indicate that a few gene variants associated with the reference values of TSH in other populations are also associated with the reference values of TSH in Iranians.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40200-023-01383-2.

The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10-8). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10-9). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10-8). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.

Wolbachia is a maternally inherited intracellular bacterium that infects a wide range of arthropods including mosquitoes. The endosymbiont is widely used in biocontrol strategies due to its capacity to modulate arthropod reproduction and limit pathogen transmission. Wolbachia infections in Culex spp. are generally assumed to be monoclonal but the potential presence of genetically distinct Wolbachia subpopulations within and between individual organs has not been investigated using whole genome sequencing. Here we reconstructed Wolbachia genomes from ovary and midgut metagenomes of single naturally infected Culex pipiens mosquitoes from Southern France to investigate patterns of intra- and inter-individual differences across mosquito organs. Our analyses revealed a remarkable degree of intra-individual conservancy among Wolbachia genomes from distinct organs of the same mosquito both at the level of gene presence-absence signal and single-nucleotide polymorphisms (SNPs). Yet, we identified several synonymous and non-synonymous substitutions between individuals, demonstrating the presence of some level of genomic heterogeneity among Wolbachia that infect the same C. pipiens field population. Overall, the absence of genetic heterogeneity within Wolbachia populations in a single individual confirms the presence of a dominant Wolbachia that is maintained under strong purifying forces of evolution.

BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS.
METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association.
RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings.
CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

BACKGROUND: Vitamin deficiencies are linked to various eye diseases, and the influence of vitamin D on cataract formation has been noted in prior research. However, detailed investigations into the causal relationship between 25-(OH)D status and cataract development remain scarce.
OBJECTIVE: To explore a possible causal link between cataracts and vitamin D.
METHODS: In this study, we explored the causal link between 25-(OH)D levels and cataract development using Mendelian randomization. Our analytical approach included inverse-variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. The primary analyses utilized IVW with random effects, supplemented by sensitivity and heterogeneity tests using both IVW and MR-Egger. MR-Egger was also applied for pleiotropy testing. Additionally, a leave-one-out analysis helped identify potentially impactful single-nucleotide polymorphisms.
RESULTS: The analysis revealed a positive association between 25-(OH)D levels and the risk of developing cataracts (OR = 1.11, 95%CI: 1.00-1.22; P = 0.032). The heterogeneity test revealed that our IVW analysis exhibited minimal heterogeneity (P > 0.05), and the pleiotropy test findings confirmed the absence of pleiotropy within our IVW analysis (P > 0.05). Furthermore, a search of the human genotype-phenotype association database failed to identify any potentially relevant risk-factor single nucleotide polymorphisms.
CONCLUSIONS: There is a potential causal link between 25-(OH)D levels and the development of cataracts, suggesting that greater 25-(OH)D levels may be a contributing risk factor for cataract formation. Further experimental research is required to confirm these findings.

Background: Hepatocellular carcinoma (HCC) is the most common and fatal primary liver cancer. Genetic variants of DNA repair systems can reduce DNA repair capability and increase HCC risk. Objectives: This study aimed to examine, in Egyptian hepatitis C virus (HCV) patients, the relationship between the X-ray repair cross-complementing group 1 (XRCC1) rs1799782 single nucleotide polymorphism (SNP) and HCC susceptibility. Methods: We included 100 adult HCV-positive patients with HCC and 100 adult HCV-positive patients with liver cirrhosis as pathological controls. XRCC1 rs1799782 SNP genotyping was done in both groups using quantitative real-time PCR (qPCR). The distribution of genotypes in patients and controls was compared using several inheritance models. Results: We found that the CT genotype, when analyzed under both the co-dominant (OR (95 % CI): 2.147 (1.184-3.893), p = .012) and the over-dominant (OR (95 % CI): 2.055 (1.153-3.660), p = .015) models, as well as the combined CT and TT genotypes under the dominant model (OR (95 % CI) of 1.991 (1.133-3.497), p = .017), were associated with increased susceptibility to HCC. The frequency of the T allele was higher among HCC participants (32%) compared to those with cirrhosis (23.5%) and carrying the T allele increased the risk of HCC by 1.532 times, however, these associations did not reach statistical significance (p-values >0.05). Moreover, the variant T allele was associated with worse clinical manifestations and laboratory results among the HCC group, but AFP levels were not affected significantly. Conclusions: Egyptians with XRCC1 rs1799782 SNP may have a higher risk of HCV-related HCC. More extensive multi-center prospective investigations must confirm this association.