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.

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer\'s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.

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Schizophrenia (SPR) is the most devastating mental illness that causes severe deterioration in social and occupational functioning, but, the etiology remains unknown. The objective of this study is to explore the genetic underpinnings of novelty seeking behavior in schizophrenic family within the Korean population. By conducting a family-based genome-wide association study, we aim to identify potential genetic markers and variations associated with novelty seeking traits in the context of SPR. We have recruited 27 probands (with SPR) with their parents and siblings whenever possible. DNA was extracted from blood sampling of 58 individuals in 27 families and analyzed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (qFAM) was used to derive SNP association values across all chromosomes. Although none of the final 800,000 SNPs reached the genome-wide significant threshold of 8.45 × 10-7, the most significant 4 SNPs were within the 10-5 to 10-7. This study identifies genetic associations between novelty seeking behavior and SPR within families. RAPGEF5 emerges as a significant gene, along with other neuropsychiatric-related genes. Noteworthy genes like DRD4 and COMT did not show associations, possibly due to the focus on schizophrenic family. While shedding light on this complex relationship, larger studies are needed for robust conclusions and deeper mechanistic insights.

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the \"microbiota\" and \"gut lymphocyte homing\" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.

Several studies have confirmed the important role of endometrial cancer (EC) in the development and progression of breast cancer (BC), and this study will explore the causal relationship between EC and BC by 2-sample Mendelian randomization analysis. Pooled data from published genome-wide association studies were used to assess the association between EC and BC risk in women using 5 methods, namely, inverse variance weighting (IVW), MR-Egger, weighted median (WME), simple multimaximetry (SM) and weighted multimaximetry (WM) with the EC-associated genetic loci as the instrumental variables (IV) and sensitivity analyses were used to assess the robustness of the results. The statistical results showed a causal association between EC and BC (IVW: OR = 1.07, 95% CI = 1.01-1.32, P = .02; MR-Egger: OR = 1.21, 95% CI = 0.71-1.51, P = .11; weighted median: OR = 1.05, 95% CI = 0.97-1.31, P = .19; simple plurality method: OR = 0.98, 95% CI = 0.81-1.15, P = .78; weighted plurality method: OR = 0.98, 95% CI = 0.81-1.14, P = .75), and the results of the sensitivity analyses showed that there was no significant heterogeneity or multiplicity, and the results were stable. EC is associated with an increased risk of developing BC. The results of this MR analysis can be used as a guideline for screening for BC in women with EC and to help raise awareness of screening for early detection and treatment.

BACKGROUND: The study of non-communicable diseases (NCDs) in a developing country like Thailand has rarely been conducted in long-term cohorts, especially among the working-age population. We aim to assess the prevalence and incidence of risk factors and their associations underlying NCDs, especially type-2 diabetes mellitus (T2DM) among healthcare workers enrolled in the Siriraj Health (SIH) study cohort.
METHODS: The SIH study was designed as a longitudinal cohort and conducted at Siriraj hospital, Thailand. A total of 5,011 participants (77% women) were recruited and follow-up. Physical examinations, blood biochemical analyses, family history assessments, behavior evaluations, and genetics factors were assessed.
RESULTS: The average age was 35.44±8.24 years and 51% of participants were overweight and obese. We observed that men were more likely to have a prevalence of T2DM and dyslipidemia (DLP) compared to women. Aging was significantly associated with pre-diabetes and T2DM (P<0.001). Additionally, aging, metabolic syndrome, and elevated triglycerides were associated with the development of pre-diabetes and T2DM. The minor T allele of the rs7903146(C/T) and rs4506565 (A/T) were associated with a high risk of developing pre-diabetes with odds ratios of 2.74 (95% confidence interval [CI]: 0.32-23.3) and 2.71 (95% CI: 0.32-23.07), respectively; however, these associations were statistically insignificant (P>0.05).
CONCLUSIONS: The findings of the SIH study provide a comprehensive understanding of the health status, risk factors, and genetic factors related to T2DM in a specific working population and highlight areas for further research and intervention to address the growing burden of T2DM and NCDs.

UNASSIGNED: Genetic factors are not included in prediction models for coronary heart disease (CHD).
UNASSIGNED: The authors assessed the predictive utility of a polygenic risk score (PRS) for CHD (defined as myocardial infarction, coronary revascularization, or cardiovascular death) and whether the risks due to monogenic familial hypercholesterolemia (FH) and family history (FamHx) are independent of and additive to the PRS.
UNASSIGNED: In UK-biobank participants, PRSCHD was calculated using metaGRS, and 10-year risk for incident CHD was estimated using the pooled cohort equations (PCE). The area under the curve (AUC) of the receiver operator curve and net reclassification improvement (NRI) were assessed. FH was defined as the presence of a pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9. FamHx was defined as a diagnosis of CHD in first-degree relatives. Independent and additive effects of PRSCHD, FH, and FamHx were evaluated in stratified analyses.
UNASSIGNED: In 323,373 participants with genotype data, the addition of PRSCHD to PCE increased the AUC from 0.759 (95% CI: 0.755-0.763) to 0.773 (95% CI: 0.769-0.777). The AUC and NRIEvent for PRSCHD were higher before the age of 55 years. Of 199,997 participants with exome sequence data, 10,000 had a PRSCHD ≥95th percentile (PRSP95), 673 had FH, and 46,163 had FamHx. The CHD risk associated with PRSP95 was independent of FH and FamHx. The risks associated with combinations of PRSCHD, FH, and FamHx were additive and comprehensive estimates could be obtained by multiplying the risk from each genetic factor.
UNASSIGNED: Incorporating PRSCHD into the PCE improves risk prediction for CHD, especially at younger ages. The associations of PRSCHD, FH, and FamHx with CHD were independent and additive.

UNASSIGNED: The comorbidity rate of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is high; nevertheless, the reasons behind this high rate remain unclear. Their similar genetic makeup probably contributes to this comorbidity.
UNASSIGNED: Based on data obtained from the genome-wide association study of IBD and RA, we first assessed an overall genetic association by performing the linkage disequilibrium score regression (LDSC) analysis. Further, a local correlation analysis was performed by estimating the heritability in summary statistics. Next, the causality between the two diseases was analyzed by two-sample Mendelian randomization (MR). A genetic overlap was analyzed by the conditional/conjoint false discovery rate (cond/conjFDR) method.LDSC with specific expression of gene analysis was performed to identify related tissues between the two diseases. Finally, GWAS multi-trait analysis (MTAG) was also carried out.
UNASSIGNED: IBD and RA are correlated at the genomic level, both overall and locally. The MR results suggested that IBD induced RA. We identified 20 shared loci between IBD and RA on the basis of a conjFDR of <0.01. Additionally, we identified two tissues, namely spleen and small intestine terminal ileum, which were commonly associated with both IBD and RA.
UNASSIGNED: Herein, we proved the presence of a polygenic overlap between the genetic makeup of IBD and RA and provided new insights into the genetic architecture and mechanisms underlying the high comorbidity between these two diseases.

Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly conducted in European populations, while Middle Eastern populations remain largely underrepresented. We conducted a GWAS on the indices of IR (HOMA2-IR) and beta cell function (HOMA2-%B) in 6,217 non-diabetic individuals from the Qatar Biobank (QBB; Discovery cohort; n = 2170, Replication cohort; n = 4047) with and without body mass index (BMI) adjustment. We also developed polygenic scores (PGS) for HOMA2-IR and compared their performance with a previously derived PGS for HOMA-IR (PGS003470). We replicated 11 loci that have been previously associated with HOMA-IR and 24 loci that have been associated with HOMA-%B, at nominal statistical significance. We also identified a novel locus associated with beta cell function near VEGFC gene, tagged by rs61552983 (P = 4.38 × 10-8). Moreover, our best performing PGS (Q-PGS4; Adj R2 = 0.233 ± 0.014; P = 1.55 x 10-3) performed better than PGS003470 (Adj R2 = 0.194 ± 0.014; P = 5.45 x 10-2) in predicting HOMA2-IR in our dataset. This is the first GWAS on HOMA2 and the first GWAS conducted in the Middle East focusing on IR and beta cell function. Herein, we report a novel locus in VEGFC that is implicated in beta cell dysfunction. Inclusion of under-represented populations in GWAS has potentials to provide important insights into the genetic architecture of IR and beta cell function.