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Background: Observational clinical studies suggest an association between dilated cardiomyopathy (DCM) and various factors including titin, cardiac troponin I (CTnI), desmocollin-2, the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency. The causal nature of these associations remains uncertain. This study aims to explore these correlations using the Mendelian randomization (MR) approach. Objective: To investigate the etiology of DCM through Mendelian randomization analysis. Methods: Data mining was conducted in genome-wide association study databases, focusing on variant target proteins (titin, CTnI, desmocollin-2), the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency, with DCM as the outcome. The analysis employed various regression models, namely, the inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode methods. Results: The IVW results showed a correlation between titin protein and DCM, identifying titin as a protective factor [OR = 0.856, 95% CI (0.744-0.985), P = 0.030]. CTnI protein correlated with DCM, marking it as a risk factor [OR = 1.204, 95% CI (1.010-1.436), P = 0.040]. Desmocollin-2 also correlated with DCM and was recognized as a risk factor [OR = 1.309, 95% CI (1.085-1.579), P = 0.005]. However, no causal relationship was found between the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, renal insufficiency, and DCM (P > 0.05). The MR-Egger intercept test indicated no pleiotropy (P > 0.05), affirming the effectiveness of Mendelian randomization in causal inference. Conclusion: Titin, CTnI, and desmocollin-2 proteins were identified as independent risk factors for DCM. Contrasting with previous observational studies, no causal relationship was observed between DCM and the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, or renal insufficiency.

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Trichomes, which originate from the epidermal cell of aerial organs, provide plants with defense and secretion functions. Although numerous genes have been implicated in trichome development, the molecular mechanisms underlying trichome cell formation in plants remain incompletely understood. Here, we using genome-wide association study (GWAS) across 1037 diverse accessions in upland cotton (Gossypium hirsutum) to identify three loci associated with leaf pubescence (hair) amount, located on chromosome A06 (LPA1), A08 (LPA2) and A11 (LPA3), respectively. GhHD1, a previously characterized candidate gene, was identified on LPA1 and encodes an HD-Zip transcription factor. For LPA2 and LPA3, we identified two candidate genes, GhGIR1 and GhGIR2, both encoding proteins with WD40 and RING domains that act as inhibitors of leaf hair formation. Expression analysis revealed that GhHD1 was predominantly expressed in hairy accessions, whereas GhGIR1 and GhGIR2 were expressed in hairless accessions. Silencing GhHD1 or overexpressing GhGIR1 in hairy accessions induced in a hairless phenotype, whereas silencing GhGIR2 in hairless accessions resulted in a hairy phenotype. We also demonstrated that GhHD1 interact with both GhGIR1 and GhGIR2, and GhGIR1 can interact with GhGIR2. Further investigation indicated that GhHD1 functions as a transcriptional activator, binding to the promoters of the GhGIR1 and GhGIR2 to active their expression, whereas GhGIR1 and GhGIR2 can suppress the transcriptional activation of GhHD1. Our findings shed light on the intricate regulatory network involving GhHD1, GhGIR1 and GhGIR2 in the initiation and development of plant epidermal hairs in cotton.

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Objective: Previous studies have reported that dietary intake is associated with immunoglobulin A nephropathy (IgAN). However, the causal relationship remains unknown. Based on publicly available genome-wide association study (GWAS) data, we conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between 26 dietary exposures and IgAN. Methods: Five methods, including inverse variance weighting (IVW), MR-Egger regression, weighted median, simple mode, and weighted mode, were applied in the MR analysis. To identify the presence of horizontal pleiotropy, we used the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Cochran's Q statistics were used to assess instrument heterogeneity. We conducted sensitivity analysis using the leave-one-out method. Results: Finally, the results indicated alcohol intake frequency (odds ratio [OR] (95% confidence interval [CI]) = 1.267 (1.100-1.460), p = 0.0010295) was a risk factor of IgAN, while cheese intake (OR (95% CI) = 0.626 (0.492-0.798), p = 0.0001559), cereal intake (OR (95% CI) = 0.652 (0.439-0.967), p = 0.0334126), and sushi intake (OR (95% CI) = 0.145 (0.021-0.997), p = 0.0497) were protective factors of IgAN. No causal relationship was found between IgAN and the rest of the dietary exposures. Conclusion: Our study provided genetic evidence that alcohol intake frequency was associated with an increased risk of IgAN, while cheese, cereal, and sushi intake were associated with a decreased risk of IgAN. Further investigation is required to confirm these results.

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BACKGROUND: The intricate interplay between genetics and immunology often dictates the host's susceptibility to various diseases. This study explored the genetic causal relationship between natural killer (NK) cell-related traits and the risk of infection. METHODS: Single-nucleotide polymorphisms (SNPs) significantly associated with NK cell-related traits were selected as instrumental variables to estimate their genetic causal effects on infection. SNPs from a genome-wide association study (GWAS) on NK cell-related traits, including absolute cell counts, median fluorescence intensities reflecting surface antigen levels, and relative cell counts, were used as exposure instruments. Summary-level GWAS statistics of four phenotypes of infection were used as the outcome data. The exposure and outcome data were analyzed via the two-sample Mendelian randomization method. RESULTS: Each one standard deviation increase in the expression level of human leukocyte antigen (HLA)-DR on HLA-DR+ NK cells was associated with a lower risk of pneumonia (P < 0.05). An increased HLA-DR+ NK/CD3- lymphocyte ratio was related to a lower of risk of pneumonia (P  < 0.05). Each one standard deviation increase in the absolute count of HLA-DR+ NK cells was associated with a lower risk of both bacterial pneumonia and pneumonia (P < 0.05). An increased HLA-DR+ NK/NK ratio was associated with a decreased risk of both pneumonia and bacterial pneumonia (P < 0.05). The results were robust under all sensitivity analyses. No evidence for heterogeneity, pleiotropy, or potential reverse causality was detected. Notably, our analysis did not reveal any significant associations between NK cell-related traits and other phenotypes of infection, including cellulitis, cystitis, and intestinal infection. CONCLUSIONS: HLA-DR+ NK cells could be a novel immune cell trait associated with a lower risk of bacterial pneumonia or pneumonia.

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OBJECTIVES: Pre-eclampsia (PE) and gestational hypertension (GH) are two different categories of hypertensive disorders of pregnancy. Given earlier observational research, the relationship between sex hormone-binding globulin (SHBG) and a higher risk of GH/PE is still up for dispute. Hence, the present investigation aimed to examine the possible link between SHBG and the likelihood of GH/PE. METHODS: As a first stage, single nucleotide polymorphisms from summary-level genome-wide association studies were tightly screened using quality-control techniques. Afterward, we utilized a two-sample Mendelian randomization (MR) study to examine the causal impact of SHBG on the likelihood of GH/PE. There was no indication of a relationship between blood SHBG level (n = 214,989) and GH/PE (1864 cases and 461,069 controls) in the initial study. Consensus results were obtained from the replicated analysis, which utilized MR estimates based on serum SHBG level(n = 214,989) for GH (4255 cases and 114,735 controls). RESULTS: The findings did not indicate any proof of a cause-and-effect connection between SHBG and the likelihood of GH/PE (odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.999 - 1.00, p = .34). Replicate analysis also revealed similar patterns (OR = 0.92, 95%CI = 0.82-1.05, p = .21). The above findings were demonstrated to have a strong level of robustness. CONCLUSIONS: The findings of this research did not offer definitive proof to endorse the idea that SHBG has a direct causal impact on the likelihood of GH/PE, which goes against numerous widely accepted observational studies. To ascertain the potential processes behind the relationships seen in observational studies, more investigation is needed.

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BACKGROUND: As precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method. RESULTS: The S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics. CONCLUSIONS: Taken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations.

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Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment.

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Introduction: Breeding rice with drought tolerance for harsh environments is crucial for agricultural sustainability. Understanding the genetic underpinnings of drought tolerance is vital for developing resilient rice varieties. Genome-wide association studies (GWAS) have emerged as pivotal tools in unravelling the complex genetic architecture of traits like drought tolerance, capitalizing on the natural genetic diversity within rice germplasm collections. Methods: In this study, a comprehensive panel of 210 rice varieties was phenotyped over ten days in controlled conditions, subjected to simulated drought stress using 20% PEG 6000 in petri dishes. Throughout the stress period, crucial traits such as germination percentage (GP), germination rate index (GRI), mean germination time (MGT), and seedling percentage (SP) were meticulously monitored. Results: The GWAS analysis uncovered a total of 38 QTLs associated with drought tolerance traits, including novel loci like qMGT-5.2, qSP-3, qSP7.2, and qGP-5.2. Additionally, RNA-seq analysis identified ten genes with significant expression differences under drought stress conditions. Notably, haplotype analysis pinpointed elite haplotypes in specific genes linked to heightened drought tolerance. Discussion: Overall, this study underscores the importance of GWAS in validating known genes while unearthing novel loci to enrich the genetic resources for enhancing drought tolerance in rice breeding programs.

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INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. HIGHLIGHTS: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

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BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. METHODS: We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. RESULTS: Case-control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. CONCLUSIONS: This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.

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Introduction: Avocado (Persea americana) is a highly nutritious fruit gaining worldwide popularity. However, its cultivation is currently reliant on a limited number of cultivars with restricted genetic diversity. This study aims to investigate the genetic diversity and population structure of avocado germplasm and identify genetic loci associated with key fruit quality traits that influence customer preference. Methods: A diversity panel of 110 avocado accessions was analyzed using 4,706 high-quality single nucleotide polymorphisms (SNPs). Genetic diversity and population structure were analyzed using pairwise FST, AMOVA, admixture analysis, and phylogenetic analysis. Genome-wide association studies (GWAS) were conducted targeting nine fruit quality traits using two models: General Linear Model (GLM) with Principal Component Analysis (PCA) and Mixed Linear Model (MLM) with PCA and kinship (PCA + K). Results: The analysis revealed three distinct populations corresponding to the three avocado ecotypes: Guatemalan, West Indian, and Mexican. Phylogenetic analysis indicated a closer relationship between the Guatemalan and West Indian races compared to the Mexican race in our Florida germplasm collection. GWAS led to identification of 12 markers within 11 genomic regions significantly associated with fruit quality traits such as fruit color, shape, taste, and skin texture. These markers explained between 14.84% to 43.96% of the phenotypic variance, with an average of 24.63%. Annotation of these genomic regions unveiled candidate genes potentially responsible for controlling these traits. Discussion: The findings enhance our understanding of genetic diversity and population structure in avocado germplasm. The identified genetic loci provide valuable insights into the genetic basis of fruit quality traits, aiding breeding programs in developing improved avocado cultivars. Marker-assisted selection can accelerate the development of new varieties, promoting a more diverse and resilient avocado market.

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BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

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BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks. METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR). RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007). CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.

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Background: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. Here, we combined high-resolution single-nuclei RNA sequencing data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder. Methods: Gene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants were tested in genes with high expression specificity for each cell type. We also explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons. Results: Common risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia genome-wide association study risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate. Conclusions: We identified a population of layer 4 glutamatergic PFC neurons likely to be particularly affected by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.

The prefrontal cortex (PFC) has been strongly implicated in the underlying biology of schizophrenia. We tested whether specific cell populations within the PFC preferentially express genes that increase risk for the disorder. We found that a particular type of PFC neuron prominently expresses genes associated with schizophrenia, suggesting its involvement in the condition.

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OBJECTIVE: To analyze genome-wide studies devoted to polymorphisms of factors of anterior abdominal wall hernias, to study the association of the most common polymorphism In Russian population. MATERIAL AND METHODS: Searching for literature data was carried out in the RSCI and PubMed databases. We enrolled national and foreign reports. The study on Russian population included 577 people. RESULTS: We found 5 genome-wide studies performed by foreign authors. We identified the loci responsible for genetic predisposition to inguinal hernias: WT1, EFEMP1, EBF2 and ADAMTS6. The Japanese scientists revealed an important role of loci TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, ATP5F1CP1/CDKN3. In other studies, loci 1q41 (ZC3H11B), 2p16.1 (EFEMP1), 6p22.1 (MHC region), 7q33 (CALD1) and 11p13 (WT1) determined different hernias. The EFEMP1 gene polymorphism was among genes most associated with anterior abdominal wall hernias in all studies. Analysis of this polymorphism In Russian population revealed significant association with anterior abdominal wall hernias. CONCLUSION: The obtained data on target correction of DNA chains can significantly reduce the incidence of anterior abdominal wall hernias. In turn, this will significantly reduce the cost of surgical treatment and risk of complications with recurrences of hernias. Moreover, identifying the most associated polymorphisms may be valuable to determine the most appropriate surgical treatment.

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INTRODUCTION: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. HIGHLIGHTS: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

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Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured mean spherical equivalent (SE), genetic, and demographic data were included. The myopia PRS was generated based on genome-wide association study (GWAS) outcomes in a Taiwanese population and previously published GWAS reports. The results demonstrated that the inclusion of age and sex in the PRS had an area under the curve (AUC) of 0.80, 0.78, and 0.73 (p < 0.001) for participants aged >18 years with high (SE < -6.0 diopters (D); n = 1089), moderate (-6.0 D < SE ≤ -3.0 D; n = 3929), and mild myopia (-3.0 D < SE ≤ -1.0 D; n = 2241), respectively. Participants in the top PRS quartile had a 1.30-fold greater risk of high myopia (95% confidence interval = 1.09-1.55, p = 0.003) compared with that in the remaining participants. Further, a higher PRS significantly increased the risk of high myopia (SE ≤ -2.0 D) in children ≤6 years of age (p = 0.027). In conclusion, including the PRS, age, and sex improved the prediction of high myopia risk in the Taiwanese population.

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For bipolar disorder (BD), the inconsistency of treatment guidelines and the long phases of pharmacological adjustment remain major challenges. BD is known to be comorbid with many medical and psychiatric conditions and they may share inflammatory and stress-related aetiologies, which could give rise to this association. The integrated stress response (ISR) responds to various stress conditions that lead to alterations in cellular homeostasis. However, as a causative mechanism underlying cognitive deficits and neurodegeneration in a broad range of brain disorders, the impact of ISR on BD is understudied. Mendelian randomization has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for BD and analyze their pathophysiological mechanisms, using the summary data-based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the summary-level data of the GWAS on BD and the expression quantitative trait locus (eQTL) study in blood. We utilized the GWAS data including 41,917 BD cases and 371,549 controls from the Psychiatric Genomics Consortium and the eQTL data from 31,684 participants of predominantly European ancestry from the eQTLGen consortium. The SMR analysis identified the EIF2B5 gene that was associated with BD due to no linkage but pleiotropy or causality. The COLOC analysis strongly suggested that EIF2B5 and the trait of BD were affected by shared causal variants, and thus were colocalized. Utilizing data in EpiGraphDB we find other putative causal BD genes (EIF2AK4 and GSK3B) to prioritize potential alternative drug targets.

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BACKGROUND: Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants. FINDINGS: We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue. INTERPRETATION: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis. FUNDING: NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.

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