Genetic Association Studies Research Articles

Genome-Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer.

Infection by high-risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large-scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome-wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case-control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene-based analysis identified HLA-DQA1 and HLA-DQB1 as genome-wide significant (GWS) genes. In validation genotyping, the genome-wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78-0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59-0.91, n = 1431). This variant was found to be a robust eQTL for HLA-DRB1, HLA-DQB1-AS1, C4B, HLA-DRB5, HLA-DRB6, HLA-DQB1, and HLA-DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty-four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type-specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.

A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.

Sickle cell disease (SCD) is the most common monogenic disease in the world and is caused by mutations in the β-globin gene (HBB). Notably, SCD is characterized by extreme clinical heterogeneity. Inter-individual variation in fetal hemoglobin (HbF) levels strongly contributes to this patient-to-patient variability, with high HbF levels associated with decreased morbidity and mortality. Genetic association studies have identified and replicated HbF levels-associated variants at three loci: BCL11A, HBS1L-MYB, and HBB. In SCD patients, genetic variation at these three loci accounts for ~ 50% of HbF heritability. Genome-wide association studies (GWAS) in non-anemic and SCD patients of multiple ancestries have identified 20 new HbF-associated variants. However, these genetic associations have yet to be replicated in independent SCD cohorts. Here, we validated the association between HbF levels and variants at five of these new loci (ASB3, BACH2, PFAS, ZBTB7A, and KLF1) in up to 3740 SCD patients. By combining CRISPR inhibition and single-cell transcriptomics, we also showed that sequences near non-coding genetic variants at BACH2 (rs4707609) and KLF1 (rs2242514, rs10404876) can control the production of the β-globin genes in erythroid HUDEP-2 cells. Finally, we analyzed whole-exome sequence data from 1354 SCD patients but could not identify rare genetic variants of large effect on HbF levels. Together, our results confirm five new HbF-associated loci that can be functionally studied to develop new strategies to induce HbF expression in SCD patients.

Lipoprotein(a) and prothrombotic effects: Evidence from a genetic association study: Prothrombotic effects of lipoprotein(a).

It is unknown whether lipoprotein(a) [Lp(a)] has prothrombotic effects contributing to its association with the risk of myocardial infarction (MI). In 410,177 participants of UK Biobank, associations of LPA genetic variants and observed Lp(a) concentrations with the risk of venous thromboembolism (VTE) and MI were investigated, stratified by scores of genetic variants influencing coagulation through the thrombin and platelet pathways (denoted as F2/F5 and GUCY1A3 scores, respectively). Risk estimates are expressed as hazard ratio (HR) and 95% confidence interval (95% CI). Neither LPA genetic variants nor observed Lp(a) concentration were associated with the risk of incident VTE (HR per 100 nmol/L higher Lp(a) 1.02, 95% CI 1.00-1.04, p=0.13). In contrast, there was a strong association with the risk of incident MI (HR per 100 nmol/L higher Lp(a) 1.31, 95% CI 1.29-1.33, p<0.001). The F2/F5 score was associated with a stepwise decrease in the risk of VTE, and the GUCY1A3 score with a stepwise decrease in the risk of MI. However, the associations of LPA genetic variants and observed Lp(a) concentrations with the risk of MI were not modified by stratification for either of the coagulation scores. The association between Lp(a) and MI was not modified by genetically determined levels of coagulation activity through the thrombin or platelet pathway. Our findings do not support the notion that the increased risk of MI caused by elevated Lp(a) is due to prothrombotic effects.

Sensitivity to Environmental Stress and Adversity and Lung Cancer

Sensitivity to environmental stress and adversity may influence lung cancer risk, highlighting a critical link between psychosocial factors and cancer etiology. To evaluate whether genetically estimated sensitivity to environmental stress and adversity is associated with lung cancer risk. Data were obtained from a genome-wide association study identifying 37 independent genetic variants strongly associated with sensitivity to environmental stress and adversity and a cross-ancestry genome-wide meta-analysis from the International Lung Cancer Consortium. Data were extracted between October 2023 and January 2024 and analyzed between February 2024 and June 2024. Genetically estimated sensitivity to environmental stress and adversity. The main outcome was lung cancer risk, and odds ratios and 95% CIs were used to assess the association between sensitivity to environmental stress and adversity with lung cancer risk. This genetic association study used a 2-sample Mendelian randomization (MR) to estimate the association between genetically estimated sensitivity to environmental stress and adversity and lung cancer risk across different histologic types. Using data from 351 827 individuals from the UK Biobank and a cross-ancestry genome-wide analysis of 61 047 lung cancer cases and 947 237 controls from the International Lung Cancer Consortium, sensitivity to environmental stress and adversity was significantly associated with an increased risk of lung cancer among individuals of European ancestry (OR, 1.49; 95% CI, 1.13-1.98; P = .005) and in the cross-ancestry analysis (OR, 1.45; 95% CI, 1.13-1.85; P = .004). There were heterogeneities in the observed associations across histologic subtypes among different population ancestries. Among individuals of European ancestry, a significant association was noted among squamous cell carcinoma (OR, 1.69; 95% CI, 1.06-2.70; P = .03). Among individuals of East Asian ancestry, an increased risk was observed for adenocarcinoma (OR, 2.04; 95% CI, 1.00-4.18; P = .05). Associations were not observed across any of the 3 histologic subtypes among individuals of African ancestry. In this genetic association study, sensitivity to environmental stress and adversity was associated with lung cancer risk. These results underscore the necessity for further research into the nuanced association between psychosocial stress and cancer risk, with a particular focus on diverse populations.

The Kidney-Immune-Brain Axis: The Role of Inflammation in the Pathogenesis and Treatment of Stroke in Chronic Kidney Disease.

Cardiovascular diseases such as stroke are a major cause of morbidity and mortality for patients with chronic kidney disease (CKD). The underlying mechanisms connecting CKD and cardiovascular disease are yet to be fully elucidated, but inflammation is proposed to play an important role based on genetic association studies, studies of inflammatory biomarkers, and clinical trials of anti-inflammatory drug targets. There are multiple sources of both endogenous and exogenous inflammation in CKD, including increased production and decreased clearance of proinflammatory cytokines, oxidative stress, metabolic acidosis, chronic and recurrent infections, dialysis access, changes in adipose tissue metabolism, and disruptions in intestinal microbiota. This review focuses on the mechanisms of inflammation in CKD, dialysis and associated therapies, its proposed impact on stroke pathogenesis and prognosis, and the potential role of anti-inflammatory agents in the prevention and treatment of stroke in patients with CKD.

P0075 Evaluation of the modulatory potential of polyphenolic compounds on intestinal inflammation at the transcriptomic level

Abstract Background Inflammatory bowel disease (IBD) is a chronic multifactorial gastrointestinal condition influenced by genetic, environmental, and immune system factors. Gut microbiota disruption plays a key role in disease onset and progression, leading to inflammation, impaired healing, and increased intestinal permeability1,2. Diet, particularly polyphenols from fruits, vegetables, and tea, can impact microbiota composition and offer anti-inflammatory benefits. This study explores the effects of these compounds on inflammation of the intestinal epithelium at the transcriptomic level. Methods A panel of polyphenolic compounds (n=8) was tested on Caco-2 cells, which were pre-treated with the metabolites before inflammation was induced for 24 h using TNF-α and IFN-γ. The effects were evaluated through targeted gene expression analysis using RT-qPCR. Prioritized compounds – Urolithin A (UroA) and Gallic Acid (GA) – were further tested on inflamed 3D colonic epithelial organoids derived from ulcerative colitis patient (UC) (n=1) and non-IBD individual (n=1), with mRNA sequencing performed on the NextSeq 550 (Illumina). Results Initial metabolite screening in Caco-2 cells was performed by analyzing the expression changes of pro-inflammatory cytokines-coding genes TNF-α, MCP-1, IL-8. Results demonstrated significant induction of cellular inflammation (p &amp;lt; 0.05) after exogenous stimullation with TNF-α and IFN-γ, which was most efficiently and consistenly reduced by GA and UroA. Therefore, GA and UroA were further selected for deeper evaluation on inflamed colonic epithelial organoids. RNA-seq revealed more pronounced cell reactivity to all treatments in UC-organoids compared to non-IBD-organoids and clear sample clustering based on treatment condition. DEA and GSEA of significantly dysregulated genes revealed interesting functional insights into potential mechanisms of action of UroA and GA. Importanly, in inflammed UC-organoids, pre-treatment with GA showed significant (FDR &amp;lt; 0.05) upregulation of pathways involved in cell junction assembly, and significant (FDR &amp;lt; 0.05) downregulation of pathways involved in metabolic processes. Together, these results suggest that GA may lead to colonic epithelial cell metabolic reprogramming in UC from energy-intensive and nucleotide-demanding processess and contribute to the resolution of inflammation and restoration of gut epithelial integrity. Conclusion In conclusion, during colonic inflammation, dietary polyphenol metabolites regulate inflammatory responses, epithelial barrier function, and energy production pathways at the transcriptomic level. Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470). References 1 Jostins, L., et al. (2012). Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582 2 Cleynen, I., et al. (2016). Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. The Lancet, 387(10014), 156-167. https://doi.org/10.1016/S0140-6736(15)00465-1

P1292 Identifying genetic markers of fibrostenosis in patients with Crohn’s disease

Abstract Background While genetics has been shown to direct wound healing responses toward healing or progressive fibrosis in liver and lung disease, attempts to identify genes involved in fibrostenotic Crohn’s disease (CD) have not been successful. This knowledge gap stems partly from the challenge to uniformly define fibrostenosis, for which the golden standard currently is surgery. We aimed to investigate the genetic basis of fibrostenotic CD by conducting a case-control genetic association study in a well-defined CD cohort, and assessing the presence of protein-coding (missense) mutations in patients carrying associated single nucleotide polymorphisms (SNPs) in interesting candidate genes through whole exome sequencing. Methods A retrospective case-control association study was performed by applying strict inclusion criteria to CD patients from three Belgian centres; early ileal fibrostenotic CD was primarily defined based on computed tomography or magnetic resonance enterography and occurring within five years following diagnosis (N = 56). The control cohort consisted of ileal CD patients without fibrostenotic or penetrating complications for a minimum of ten years (N = 252). Previously collected Immunochip data were subjected to logistic regression analysis correcting for disease location and the first five principal components. Exome sequencing of patients homozygous for at least one of the three top associated SNPs was performed. Genes in the proximity of the top SNPs, along with other candidate genes based on literature, were screened for the presence of missense mutations via Integrative Genomics Viewer. Mutations were evaluated for functional impact (PolyPhen-2) and evolutionary conservation (PhyloP), and frequencies were compared with European population data (ALFA dataset). Results Eight SNPs were associated with fibrostenosis (P&amp;lt;5e-05, Table 1), and three SNPs (rs6061883, rs9372122, and rs13176097) reached suggestive significance (P&amp;lt;10-6). The two top SNPs were located in cadherin 4 and autophagy related 5, two genes known to contribute to fibrosis.1, 2 We observed a significant shorter time to fibrosis between patients with a high amount (&amp;gt;3) of risk alleles (of the top eight associated SNPs), compared to patients with a low amount (&amp;lt;3). (P&amp;lt;0.001, Figure 1). Exome sequencing data of patients carrying associated SNPs revealed high risk variants (Table 2) in several candidate genes, including autophagy related 9B, epidermal growth factor receptor, and mitogen-activated protein kinase kinase kinase 1. Conclusion This carefully phenotyped association study reveals interesting SNPs and candidate genes to further study the genetic basis of early development of fibrostenosis in ileal CD.

OP03 Mapping the observable IBDverse: Using massive-scale single-cell RNA sequencing of gut and blood samples to nominate genes, cell types and pathways driving IBD susceptibility

Abstract Background Genome-wide association studies (GWAS) have identified 370 loci associated with inflammatory bowel disease (IBD) susceptibility1. The majority of these are driven by non-coding variants, thought to dysregulate the expression of a nearby gene. The dysregulated disease effector gene, and the operative cell-type(s) is often unknown. Previous efforts to nominate effector genes have relied on identifying expression quantitative trait loci (eQTL) and expression-linked genes (eGenes). However, gene expression is often derived from healthy individuals, a single, non-primary site, and measured using bulk RNA sequencing. This likely misses cell-, site-, or disease-specific genetic effects, and has nominated disease effector genes for only a minority of IBD loci. Methods To better characterise the universe of IBD effector genes, we created IBDverse - the largest collection of single-cell RNAseq data from the terminal ileum (TI, nCD=119, nHealthy=243), rectum (nHealthy=275) and blood (nCD=95) - a total of &amp;gt;2.4 million high quality transcriptomes from 732 samples across 396 individuals. After grouping cells into different cell types, we mapped genetic variants associated with gene expression changes. Disease effector genes were nominated by identifying expression-linked genetic effects likely driven by the same causal variant as an IBD GWAS signal, as determined by colocalisation analysis2. Results Across all tissues, we identify 102 transcriptionally distinct cell types (Fig 1), and genetic effects associated with the expression of &amp;gt;17,000 genes. For 507 genes, the genetic association for their expression was strongly associated with genetic effects for IBD susceptibility, suggesting them to be drivers of disease risk. Remarkably, this doubles the previous best efforts to nominate disease effector genes3, doing so at &amp;gt;52% of IBD susceptibility loci. As well as their nomination, this study also helps contextualise disease effector expression variation. Disease effector genes were detectable in only a single tissue or cell annotation in &amp;gt;40% of cases, highlighting the need for high resolution data obtained across multiple tissues. We also find the first evidence for upregulation of RASGRP1, a gene previously correlated with exacerbated colitis in mice4, to drive Crohn’s disease susceptibility. As this is identified in a subset of tissue-resident memory T cells, and only from the TI, this also suggests this cell type and tissue as governing this effect. Conclusion This study serves as a step change in the understanding of cellular heterogeneity of these tissues, provides a compendium of genetic regulatory effects across constituent cell types, and quantifies the relevance of these to IBD susceptibility. References Liu et al., (2023). Nat. Genetics. ‘Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries’ Giambartolemi et al., (2014) PLOS Genetics. ‘Bayesian test for colocalisation between pairs of genetic association studies using summary statistics’ Panousis et al., (2024) Nat. Comms (in press). Wang et al., (2022) Nat. Comms. ‘RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth’

Subcontinental Genetic Diversity in the All of Us Research Program: Implications for Biomedical Research.

The All of Us Research Program ( All of Us ) seeks to accelerate biomedical research and address the underrepresentation of minorities by recruiting over one million ethnically diverse participants across the United States. A key question is how self-identification with discrete, predefined race and ethnicity categories compares to genetic diversity at continental and subcontinental levels. To contextualize the genetic diversity in All of Us , we analyzed ∼2 million common variants from 230,016 unrelated whole genomes using classical population genetics methods, alongside reference panels such as the 1000 Genomes Project, Human Genome Diversity Project, and Simons Genome Diversity Project. Our analysis reveals that participants within self-identified race and ethnicity groups exhibit a gradient of genetic diversity rather than discrete clusters. The distributions of continental and subcontinental ancestries show considerable variation within race and ethnicity, both nationally and across states, reflecting the historical impacts of U.S. colonization, the transatlantic slave trade, and recent migrations. All of Us samples filled most gaps along the top five principal components of genetic diversity in current global reference panels. Notably, "Hispanic or Latino" participants spanned much of the three-way (African, Native American, and European) admixture spectrum. Ancestry was significantly associated with body mass index (BMI) and height, even after adjusting for socio-environmental covariates. In particular, West-Central and East African ancestries showed opposite associations with BMI. This study emphasizes the importance of assessing subcontinental ancestries, as the continental approach is insufficient to control for confounding in genetic association studies.

Genetic Analysis of Retinal Cell Types in Neuropsychiatric Disorders

As an accessible part of the central nervous system, the retina provides a unique window to study pathophysiological mechanisms of brain disorders in humans. Imaging and electrophysiological studies have revealed retinal alterations across several neuropsychiatric and neurological disorders, but it remains largely unclear which specific cell types and biological mechanisms are involved. To determine whether specific retinal cell types are affected by genomic risk for neuropsychiatric and neurological disorders and to explore the mechanisms through which genomic risk converges in these cell types. This genetic association study combined findings from genome-wide association studies in schizophrenia, bipolar disorder, major depressive disorder, multiple sclerosis, Parkinson disease, Alzheimer disease, and stroke with retinal single-cell transcriptomic datasets from humans, macaques, and mice. To identify susceptible cell types, Multi-Marker Analysis of Genomic Annotation (MAGMA) cell-type enrichment analyses were applied and subsequent pathway analyses performed. The cellular top hits were translated to the structural level using retinal optical coherence tomography (acquired between 2009 and 2010) and genotyping data in the large population-based UK Biobank cohort study. Data analysis was conducted between 2022 and 2024. Cell type-specific enrichment of genetic risk loading for neuropsychiatric and neurological disorder traits in the gene expression profiles of retinal cells. Expression profiles of amacrine cells (interneurons within the retina) were robustly enriched in schizophrenia genetic risk across mammalian species and in different developmental stages. This enrichment was primarily driven by genes involved in synapse biology. Moreover, expression profiles of retinal immune cell populations were enriched in multiple sclerosis genetic risk. No consistent cell-type associations were found for bipolar disorder, major depressive disorder, Parkinson disease, Alzheimer disease, or stroke. On the structural level, higher polygenic risk for schizophrenia was associated with thinning of the ganglion cell inner plexiform layer, which contains dendrites and synaptic connections of amacrine cells (B, -0.09; 95% CI, -0.16 to -0.03; P = .007; n = 36 349; mean [SD] age, 57.50 [8.00] years; 19 859 female [54.63%]). Higher polygenic risk for multiple sclerosis was associated with increased thickness of the retinal nerve fiber layer (B, 0.06; 95% CI, 0.02 to 0.10; P = .007; n = 36 371; mean [SD] age, 57.51 [8.00] years; 19 843 female [54.56%]). This study provides novel insights into the cellular underpinnings of retinal alterations in neuropsychiatric and neurological disorders and highlights the retina as a potential proxy to study synaptic pathology in schizophrenia.

Renin-independent aldosteronism and metabolic dysfunction-associated steatotic liver disease and cirrhosis: A genetic association study.

Renin-independent aldosteronism (RIA) refers to a spectrum of autonomous aldosterone hypersecretion. We aimed to explore the genetical relationship between RIA and metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis. We included 125357 participants from the cohort of United Kingdom Biobank. We calculated a polygenic risk score (PRS) for RIA on the basis of reported data from genome-wide association studies, and performed an analysis of Phenome Wide Association Studies (PheWAS) on diverse outcomes. We explored the genetical relationship between RIA and MASLD or cirrhosis by using Mendelian randomization analysis. An increased RIA PRS was associated with higher risks of MASLD and MASLD related cirrhosis, and the well-defined RIA related target organ damages such as hypertension or kidney diseases was also significant in the PheWAS analysis. When compared to individuals with low RIA PRS (tertile 1, 0.41-9.89), those with high RIA PRS (tertile 3, 13.58-23.16) showed significantly higher odds ratio (OR) of MASLD (OR 1.28, 95% confidence interval [CI] 1.09-1.49) and cirrhosis (OR 1.49, 95%CI 1.03-2.16). In analyses of two-sample Mendelian randomization, genetically predicted RIA significantly correlated with elevated risks of MASLD and cirrhosis (inverse variance weighted odds ratio [95% CI]: 1.05 [1.01-1.09]) for MASLD, 1.08 [1.02-1.13] for cirrhosis), meanwhile we observed no significant directional pleiotropy or heterogeneity. Renin-independent aldosteronism is genetically associated with higher risks of MASLD and cirrhosis. Targeted treatment of autonomous aldosterone secretion may alleviate MASLD progression.

Mating system of Biomphalaria sudanica, a vector of Schistosoma mansoni.

Biomphalaria snails are intermediate hosts for schistosome parasites, which cause morbidity and mortality in humans worldwide. We aimed to determine the mating system of Biomphalaria sudanica, a hermaphroditic vector of schistosomiasis in the African Great Lakes, with the goal of informing the design of genetic studies such as linkage mapping to improve genome assembly and genetic association studies to identify snail resistance genes. To determine the relative rates of outcrossing versus selfing, we assayed the progeny of experimental crosses of snails in the laboratory using a PCR and restriction enzyme digest to determine snail genotype and parentage. Out of 7 experimental crosses and 56 total offspring assayed, 100% were derived from outcrossing rather than inbreeding. These results indicate that B. sudanica is primarily an outcrossing species, although previous work has shown that this species retains the capability of self-fertilization.

A genome-wide scan of non-coding RNAs and enhancers for refractive error and myopia

Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches. We performed a genetic association study between variants in non-coding RNAs and enhancers, and RE and myopia. We obtained single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA-binding sites, long non-coding RNAs genes (lncRNAs) and enhancers from publicly available databases: miRNASNPv2, PolymiRTS, VISTA Enhancer Browser, FANTOM5 and lncRNASNP2. We investigated whether SNPs overlapping these elements were associated with RE and myopia leveraged from a large GWAS meta-analysis (N = 160,420). With genetic risk scores (GRSs) per element, we investigated the joint effect of associated variants on RE, axial length (AL)/corneal radius (CR), and AL progression in an independent child cohort, the Generation R Study (N = 3638 children). We constructed a score for biological plausibility per SNP in highly confident miRNA-binding sites and enhancers in chromatin accessible regions. We found that SNPs in two miRNA genes, 14 enhancers and 81 lncRNA genes in chromatin accessible regions and 54 highly confident miRNA-binding sites, were in RE and myopia-associated loci. GRSs from SNPs in enhancers were significantly associated with RE, AL/CR and AL progression. GRSs from lncRNAs were significantly associated with all AL/CR and AL progression. GRSs from miRNAs were not associated with any ocular biometric measurement. GRSs from miRNA-binding sites showed suggestive but inconsistent significance. We prioritized candidate miRNA binding sites and candidate enhancers for future functional validation. Pathways of target and host genes of highly ranked variants included eye development (BMP4, MPPED2), neurogenesis (DDIT4, NTM), extracellular matrix (ANTXR2, BMP3), photoreceptor metabolism (DNAJB12), photoreceptor morphogenesis (CHDR1), neural signaling (VIPR2) and TGF-beta signaling (ANAPC16). This is the first large-scale study of non-coding RNAs and enhancers for RE and myopia. Enhancers and lncRNAs could be of large importance as they are associated with childhood myopia. We provide a confident blueprint for future functional validation by prioritizing candidate miRNA binding sites and candidate enhancers.

Uncovering the Role of ALDH1A2 in Prostate Cancer: Insights from Genetic and Expression Analyses.

Biochemical recurrence (BCR) is a critical concern in prostate cancer management; however, its underlying genetic determinants remain poorly understood. The aldehyde dehydrogenase 1 (ALDH1) gene family is involved in cellular detoxification and biosynthetic processes and has been implicated in various cancers. This study investigated the association between the ALDH1 family members and prostate cancer recurrence. We conducted a two-stage genetic association study involving 134 single-nucleotide polymorphisms within the ALDH1 family to assess their association with BCR-free survival in prostate cancer. Gene set and pathway enrichment analyses were performed to explore the biological relevance of significant genes across multiple datasets. ALDH1A2 rs16939929 showed a robust association with BCR-free survival in both discovery and replication cohorts. Functional analyses indicated that rs16939929 affected ALDH1A2 expression in various tissues. Pooled analysis of 42 prostate cancer gene expression datasets revealed that ALDH1A2 expression was significantly lower in prostate cancer tissues and higher expression was associated with better patient prognosis. Enrichment analyses revealed that ALDH1A2 was co-expressed with genes primarily involved in cell adhesion pathways. Further analysis confirmed that several of these co-expressed cell adhesion molecules were associated with improved patient survival. In addition, ALDH1A2 expression was associated with increased immune cell infiltration into the prostate cancer microenvironment. In conclusion, ALDH1A2 rs16939929 is a significant predictor of BCR-free survival in prostate cancer, potentially through its effects on the gene expressions of ALDH1A2 and cell adhesion molecules. These findings suggest that ALDH1A2 plays a tumor-suppressive role in prostate cancer progression.

Genetic diversity and character association studies for agro-morphological and quality traits of advanced breeding lines in field pea (Pisum sativum L.)

Abstract The present study analysed the trait associations and the genetic diversity for morphological and qualitative traits among the 23 field pea genotypes using multivariate analysis. The correlation analysis revealed that traits like primary branches per plant, pod length, seeds per pod, harvest index and biological seed yield per plant showed a note-worthy positive association at both genotypic and phenotypic levels. Path analysis revealed the correlation of pod length, harvest index and biological yield per plant was due to direct positive effects. The principal component analysis indicated that the fiseven PCs together accounted for 86.56% of the total diversity. The cluster analysis classified genotypes into five different clusters with cluster 1 comprising 18 genotypes, cluster 2 with 2 genotypes, and the remaining three mono-genotypic clusters. The selection of diverse genotypes superior in traits with positive influence on yield can result in greater genetic gains and aid in crop improvement. Keywords: Genetic diversity, correlation, path analysis, PCA

Genetic variability and association studies for yield and pre-harvest sprouting traits in greengram [Vigna radiata (L.) Wilczek

Abstract The present study investigates the genetic variability and associations of agronomic traits impacting pre-harvest sprouting (PHS) in 30 greengram genotypes. Significant variability was observed across multiple traits, with seed yield per plant ranging from 2.19 to 7.82 g. ​Key findings indicate that hard seed percentage and alpha-amylase activity at different germination intervals are having high heritability, demonstrating genetic heritability essential for breeding strategies.​ High phenotypic variability suggests environmental influence on trait expression, especially in traits such as days to maturity and pod diameter. Correlation analysis revealed robust positive associations between seed yield and days to maturity, while negative correlations were noted with epicuticular wax content and pod wall thickness. The path analysis identified that days to 50 % flowering, along with alpha-amylase activity, directly affects yield, emphasizing the intricacies of trait interrelationships. This research aims to contribute towards developing PHS-resistant mung bean varieties that enhance crop yield and quality. Keywords: Greengram, genetic variability, pre-harvest sprouting, correlation analysis, path analysis

Alcohol Use Disorder Polygenic Score Compared With Family History and ADH1B

Identification of individuals at high risk of alcohol use disorder (AUD) and subsequent application of prevention and intervention programs has been reported to decrease the incidence of AUD. The polygenic score (PGS), which measures an individual's genetic liability to a disease, can potentially be used to evaluate AUD risk. To assess the estimability and generalizability of the PGS, compared with family history and ADH1B, in evaluating the risk of AUD among populations of European ancestry. This genetic association study was conducted between October 1, 2023, and May 21, 2024. A 2-stage design was used. First, the pruning and thresholding method was used to calculate PGSs in the screening stage. Second, the estimability and generalizability of the best PGS was determined using 2 independent samples in the testing stage. Three cohorts ascertained to study AUD were used in the screening stage: the Collaborative Study on the Genetics of Alcoholism (COGA), the Study of Addiction: Genetics and Environment (SAGE), and the Australian Twin-Family Study of Alcohol Use Disorder (OZALC). The All of Us Research Program (AOU), which comprises participants with diverse backgrounds and conditions, and the Indiana Biobank (IB), consisting of Indiana University Health system patients, were used to test the best PGS. For the COGA, SAGE, and OZALC cohorts, cases with AUD were determined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fifth Edition (DSM-5) criteria; controls did not meet any criteria or did not have any other substance use disorders. For the AOU and IB cohorts, cases with AUD were identified using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) codes; controls were aged 21 years or older and did not have AUD. The PGS was calculated using single-nucleotide variants with concordant effects in 3 large-scale genome-wide association studies of AUD-related phenotypes. The main outcome was AUD determined with DSM-IV or DSM-5 criteria and ICD-9 or ICD-10 codes. Generalized linear mixed models and logistic regression models were used to analyze related and unrelated samples, respectively. The COGA, SAGE, and OZALC cohorts included a total of 8799 samples (6323 cases and 2476 controls; 50.6% were men). The AOU cohort had a total of 116 064 samples (5660 cases and 110 404 controls; 60.4% were women). The IB cohort had 6373 samples (936 cases and 5437 controls; 54.9% were women). The 5% of samples with the highest PGS in the AOU and IB cohorts were approximately 2 times more likely to develop AUD (odds ratio [OR], 1.96 [95% CI, 1.78-2.16]; P = 4.10 × 10-43; and OR, 2.07 [95% CI, 1.59-2.71]; P = 9.15 × 10-8, respectively) compared with the remaining 95% of samples; these ORs were comparable to family history of AUD. For the 5% of samples with the lowest PGS in the AOU and IB cohorts, the risk of AUD development was approximately half (OR, 0.53 [95% CI, 0.45-0.62]; P = 6.98 × 10-15; and OR, 0.57 [95% CI, 0.39-0.84]; P = 4.88 × 10-3) compared with the remaining 95% of samples; these ORs were comparable to the protective effect of ADH1B. PGS had similar estimabilities in male and female individuals. In this study of AUD risk among populations of European ancestry, PGSs were calculated using concordant single-nucleotide variants and the best PGS was tested in targeted datasets. The findings suggest that the PGS may potentially be used to evaluate AUD risk. More datasets with similar AUD prevalence as in general populations are needed to further test the generalizability of PGS.

Case-control association study between polygenic risk score and COVID-19 severity in a Russian population using low-pass genome sequencing.

The course of COVID-19 is highly variable, with genetics playing a significant role. Through large-scale genetic association studies, a link between single nucleotide polymorphisms and disease susceptibility and severity was established. However, individual single nucleotide polymorphisms identified thus far have shown modest effects, indicating a polygenic nature of this trait, and individually have limited predictive performance. To address this limitation, we investigated the performance of a polygenic risk score model in the context of COVID-19 severity in a Russian population. A genome-wide polygenic risk score model including information from over a million common single nucleotide polymorphisms was developed using summary statistics from the COVID-19 Host Genetics Initiative consortium. Low-coverage sequencing (5x) was performed for ~1000 participants, and polygenic risk score values were calculated for each individual. A multivariate logistic regression model was used to analyse the association between polygenic risk score and COVID-19 outcomes. We found that individuals in the top 10% of the polygenic risk score distribution had a markedly elevated risk of severe COVID-19, with adjusted odds ratio of 2.9 (95% confidence interval: 1.8-4.6, p-value = 4e-06), and more than four times higher risk of mortality from COVID-19 (adjusted odds ratio = 4.3, p-value = 2e-05). This study highlights the potential of polygenic risk score as a valuable tool for identifying individuals at increased risk of severe COVID-19 based on their genetic profile.

Genetic variability and association studies in F2 populations of Groundnut (Arachis hypogaea L.)

Groundnut is an extensively self-pollinating crop with a narrow genetic base; therefore, it relies on the F2 generation for optimal segregation and recombination. The genetic variability resulting from segregation and re- combination is essential for effective selection in crop improvement pro- grammes. F2 populations derived from the crosses BSR 2 × GPBD 4 and BSR 2 × TMV 2 were assessed for examining genetic variation, and correla- tion coefficients along path coefficients. Twenty-four yield-attributing, physiological, as well as biochemical characteristics were covered in the research, in the Kharif season of 2024. The assessment of the PCV along with GCV revealed that a majority of yield-related traits, including the number of pods, kernels, and pod yield, demonstrated high PCV along with GCV in both crosses, indicating substantial genetic variation. Regarding yield-related characteristics, high GAM along with high heritability in a broad sense were noted for both the crosses, suggesting that a breeding approach based on simple selection can be successful in increasing groundnut yield. Correla- tion and path coefficients indicated that the number of mature kernels and pod yield calculated for each plant possessed a high positive direct effect on kernel yield. Transgressive segregants were identified over twice the stand- ard deviation of the better parent mean for various traits. These findings can serve as a foundation for future breeding programmes aimed at enhancing the yield and oil content.

What is new in the pathogenesis and treatment of IgA glomerulonephritis.

Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment of the chronic kidney disease, associated with the nephropathy, is mandatory, since the beginning of the disease. The classical immunosuppressive agents have poor effect. The corticosteroids remain an important cornerstone in any phase of the disease. More effect is related to the treatment of B cells and plasma cells. In particular, in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents. Most of these studies are to date in phase II/III. Finally, new agents targeting complement are arising. These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.