GWAS Analysis Research Articles

Genetic Dissection of Anthocyanin Accumulation in Tomato Using GWAS and Hybridization Probe Melting (HPM) for Marker-Assisted Breeding

Tomato fruit color is primarily influenced by the accumulation of pigments such as carotenoids and anthocyanins, which are regulated by a complex network of genes and environmental factors. The presence of anthocyanins, in particular, contributes to the purple phenotype in tomatoes, which has been associated with improved nutritional quality and disease resistance. Previous studies have identified key regulatory genes, including SlMYBATV and SlANT1, that control anthocyanin biosynthesis in tomatoes. A total of 48 tomato accessions were selected, including both anthocyanin-producing and non-producing cultivars, to assess genetic variation in relation to fruit color. GWAS analysis identified significant associations between single-nucleotide polymorphisms (SNPs) on chromosomes 7 and 10 and the purple fruit phenotype. These genomic regions contained key anthocyanin regulatory genes, SlMYBATV on chromosome 7 and SlANT1 on chromosome 10, confirming their roles in anthocyanin biosynthesis. Linkage disequilibrium (LD) analysis further revealed strong correlations between SNPs within these regions, facilitating the selection of representative SNPs for genotyping. The genotyping of SNPs Ch07_60981501 and Ch10_64354129 using HPM demonstrated clear differentiation between purple and non-purple cultivars based on melting temperature differences, validating the functional significance of the identified loci. The results confirmed that the nonfunctional SlMYBATV allele at the atv locus allows for enhanced anthocyanin accumulation by relieving repression of anthocyanin activators like SlANT1. This interaction between the Aft and atv loci drives light-dependent anthocyanin biosynthesis in purple tomatoes. HPM genotyping offers a cost-effective tool for allele identification, supporting breeding programs for anthocyanin-rich tomatoes. SNP markers enable marker-assisted selection (MAS) for improved nutritional and aesthetic traits. This study highlights SlMYBATV and SlANT1 in anthocyanin biosynthesis, advancing efforts to develop enriched tomato varieties and supporting agricultural productivity and health.

Integration of GWAS and Co-Expression Network Analysis Identified Main Genes Responsible for Nitrogen Uptake Traits in Seedling Waxy Corn

Integration of GWAS and Co-Expression Network Analysis Identified Main Genes Responsible for Nitrogen Uptake Traits in Seedling Waxy Corn

OP30 Dissecting the genetic basis of clinical phenotype heterogeneity within IBD in more than 63,000 IBD patients

Abstract Background More than 200 genetic variants associated with Inflammatory Bowel Disease (IBD) susceptibility are known but few large-scale studies have been performed to examine the genetics basis of the heterogeneity of clinical phenotypes in IBD, including disease location, behavior, age of diagnosis as well as the distinction between Crohn’s Disease (CD) and Ulcerative Colitis (UC). Our aim was to examine the genetic association with IBD clinical phenotypes in the large International IBD Genetics Consortium(IIBDGC) GWAS cohorts. Methods Details of the sample recruitment, genotyping and quality control(QC) have been described previously. In brief, genome-wide genotyping was performed in more than 20 cohorts across the world and imputation was performed using the TopMed server. Clinical phenotype data, including CD/UC (ulcerative colitis) status, disease location, behavior as well as need for surgery, were collected following the IIBDGC core phenotype standard based on widely used Montreal classifications. Association analysis was performed using Regenie. All subjects gave informed consent after IRB approval. Results Currently 63,836 IBD cases (26,648 UC and 37,188 CD) were included in the analyses. In the CDvsUC comparison, 146 independent regions were identified and 20 of those have not been associated with IBD before (e.g., JAK1, Beta = -0.40, P=7.10E-9; IL12RB1, Beta = 0.0.097, P=2.06E-14). We also identified multiple novel association with disease location and behavior (e.g., COL24A1 with stricturing CD, Beta = 0.257, P=6.52E-8; MYOCD with CD disease location, Beta = 0.507, P = 7.09E-8; MSH5-SAPCD1 with extensive disease in UC, Beta=-0.465, P=6.39E-11). Variants at NOD2 and HLA are strongly associated with multiple clinical phenotypes including CDvsUC, CD disease location and behavior as well as age of onset. Further curation of the clinical phenotypes is on-going to further boost sample size and post-GWAS analyses including fine-mapping, pathway analysis and overlap with functional data is underway. Conclusion Using a large IBD cohort, we observed strong and novel association with IBD clinical phenotypes. This largest GWAS analysis on IBD clinical phenotypes will help to better understand the genetic basis of heterogeneity in IBD clinical phenotypes and provide insights for biomarkers and novel drug targets.

Common Ancestry of the Id Locus: Chromosomal Rearrangement and Polygenic Possibilities.

The diversity in dermal pigmentation and plumage color among domestic chickens is striking, with Black Bone Chickens (BBC) particularly notable for their intense melanin hyperpigmentation. This unique trait is driven by a complex chromosomal rearrangement on chromosome 20 at the Fm locus, resulting in the overexpression of the EDN3 (a gene central to melanocyte regulation). In contrast, the inhibition of dermal pigmentation is regulated by theId locus. Although prior studies using genetic crosses, GWAS, and gene expression analysis have investigated the genetic underpinnings of the Id locus, its precise location and functional details remain elusive. Our study aims to precisely locate the Id locus, identify associated chromosomal rearrangements and candidate genes influencing dermal pigmentation, and examine the ancestral status of the Id locus in BBC breeds. Using public genomic data from BBC and non-BBC breeds, we refined the Id locus to a ~1.6Mb region that co-localizes with Z amplicon repeat units at the distal end of the q-arm of chromosome Z within a 10.36Mb inversion in Silkie BBC. Phylogenetic and population structure analyses reveal that the Id locus shares a common ancestry across all BBC breeds, much like the Fm locus. Selection signatures and highly differentiated BBC-specific SNPs within the MTAP gene position it as the prime candidate for the Id locus with CCDC112 and additional genes, suggesting a possible polygenic nature. Our results suggest that the Id locus is shared among BBC breeds and may function as asupergene cluster in shank and dermal pigmentation variation.

A Genome-Wide Association Screen for Genes Affecting Leaf Trichome Development and Epidermal Metal Accumulation in Arabidopsis.

To identify novel genes engaged in plant epidermal development, we characterized the phenotypic variability of rosette leaf epidermis of 310 sequenced Arabidopsis thaliana accessions, focusing on trichome shape and distribution, compositional characteristics of the trichome cell wall, and histologically detectable metal ion distribution. Some of these traits correlated with cLimate parameters of our accession's locations of origin, suggesting environmental selection. A novel metal deposition pattern in stomatal guard cells was observed in some accessions. Subsequent GWAS analysis identified 1546 loci with protein sequence-altering SNPs associated with one or more traits, including 5 genes with previously reported relevant mutant phenotypes and 80 additional genes with known or predicted roles in relevant developmental and cellular processes. Some candidates, including GFS9/TT9, exhibited environmentally correlated allele distribution. Several large gene famiLies, namely DUF674, DUF784, DUF1262, DUF1985, DUF3741, cytochrome P450, receptor-Like kinases, Cys/His-rich C1 domain proteins and formins were overrepresented among the candidates for various traits, suggesting epidermal development-related functions. A possible participation of formins in guard cell metal deposition was supported by observations in available loss of function mutants. Screening of candidate gene lists against the STRING interactome database uncovered several predominantly nuclear protein interaction networks with possible novel roles in epidermal development.

Integrating genetics and transcriptomics to characterize shared mechanisms in digestive diseases and psychiatric disorders

Digestive and psychiatric disorders tend to co-occur, yet mechanisms remain unclear. Leveraging genetic and transcriptomic data integration, we conduct multi-trait analysis of GWAS (MTAG) and weighted gene co-expression network analysis (WGCNA) to explore shared mechanism between psychiatric and gastrointestinal disorders. Significant genetic correlations were found between these disorders, especially in irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), depression (DEP), and neuroticism (NE). MTAG identify 60 novel pleiotropic loci for IBS and 14 for GERD, predominantly located near genes associated with neurological pathways. Further WGCNA identifies multiple co-expression modules enriched with genes involved in neurological pathways in digestive tissues, with some modules strongly preserved across brain and digestive tissues. Moreover, our network analysis suggests BSN, CELF4, and NRXN1 as central players in the regulation of the gut-brain axis (GBA). This study enhances our understanding of the GBA and underscores BSN, CELF4, and NRXN1 as crucial targets for future research.

Identification of a candidate sex determination region and sex-specific molecular markers based on whole-genome re‑sequencing in the sea star Asterias amurensis.

Sex determination systems are diverse in echinoderms, however, our understanding is still very limited in this research field, especially for Asteroidea species. The northern Pacific seastar, Asterias amurensis, has attracted widespread concern due to its population outbreaks and high-risk invasions. Using whole-genome re-sequencing data from 40 females and 40 males, we identified a candidate sex determination region in A. amurensis. Based on the distribution characteristics of 525 sex-associated single nucleotide polymorphisms, identified by GWAS analysis, 119 sex-specific loci were isolated combining a custom Perl script, PCA analysis and the selection signatures of fixation index FST, suggesting that a 7-12Mb region on chromosome 10 is a candidate sex-determining region. The existence of female-specific sequences and the genotypes of sex-specific loci indicated that A. amurensis might utilize a ZZ/ZW sex determination system. We also developed two pairs of sex-specific primers which could distinguish the genetic sex of this starfish with 100% accuracy. As the first study on sex determination in Asteroidea, it will provide novel insights into diverse sex determination systems in echinoderms and allow for in-depth studies on sex-related eco-physiological issues in A. amurensis.

Integrated Analysis of Bulk RNA Sequencing, eQTL, GWAS, and Single-Cell RNA Sequencing Reveals Key Genes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a continual therapeutic challenge owing to its elevated incidence and unfavourable prognosis, underscoring the critical need for the discovery of new molecular targets for detection and therapy. This work included the analysis of three publically accessible HCC datasets from TCGA and GEO. Instrumental variables (IVs) were derived via expression quantitative trait loci (eQTL) analysis, then followed by two-sample Mendelian randomisation (MR) analysis utilising publically available summary statistics. Key disease-associated genes were identified by assessing odds ratios and connecting them with differentially expressed genes across the datasets. The potential molecular mechanisms of these genes were clarified by functional enrichment analysis, clinical data analysis, single-cell RNA sequencing, GSEA, immune cell infiltration, and immune checkpoint analysis. These findings were then confirmed by Western blotting, immunohistochemistry, and quantitative PCR. By synthesising the outcomes from differential analysis of the databases, we found two genes, SERPING1 and STEAP3, that may be crucial in the beginning and development of HCC. These genes have a role in vital biological pathways and functions, such as metabolic regulation and macrophage activation. The significance of immunological-mediated processes in HCC was further highlighted by CIBERSORT analysis, which revealed a specific pattern of immune cell infiltration and the location of immunological checkpoints in the illness. The findings elucidate the molecular mechanisms of HCC and underscore critical genes implicated in its pathogenesis. SERPING1 and STEAP3 affect tumour cells and modify the tumour microenvironment (TME), indicating that targeting these genes may offer a viable immunotherapeutic approach for HCC in clinical settings.

Integrated GWAS, BSA-seq, and RNA-seq analyses to identify candidate genes associated with male fertility trait in peach.

Male sterility in peach (Prunus persica L.), characterized by the absence of fertile pollen grains in the anther, is determined by a recessive allele in homozygosis of the major gene located on chromosome 6. Developing tightly linked molecular markers can help identify appropriate peach parents or male-sterile plants for early culling in segregating progenies, thereby increasing breeding efficiency. In this study, we performed comprehensive research integrating genome-wide association study, bulked segregant analysis, and tissue-specific transcriptome sequencing for precisely characterizing the genes associated with male sterility and fertility in peach. We identified the candidate gene Prupe.6G027000, which encodes an ATP-binding cassette transporter G family member 26 (ABCG26), as a reliable candidate for controlling the targeted traits, as indicated by gene expression profiling and validated by quantitative real-time polymerase chain reaction, in situ hybridization, and virus-induced gene silencing. Prupe.6G027000 was transcribed preferentially on the tapetum and microspore surface, and its transient silencing caused severe pollen abortion in peach. The genotypes of nonsynonymous single-nucleotide variation (T>C) harbored in the coding region of Prupe.6G027000 exhibited approximately 96.2% consistency with male fertile or sterile phenotype in 579 peach accessions. These findings lay the foundation for dissecting the genetic basis of male fertility traits, and facilitating the establishment of a marker-assisted selection system in peaches.

GWAS analysis revealed genomic loci and candidate genes associated with the 100-seed weight in high-latitude-adapted soybean germplasm.

In the present study, we identified 22 significant SNPs, eight stable QTLs and 17 potential candidate genes associated with 100-seed weight in soybean. Soybean is an economically important crop that is rich in seed oil and protein. The 100-seed weight (HSW) is a crucial yield contributing trait. This trait exhibits complex inheritance regulated by many genes and is highly sensitive to environmental factors. In this study, an integrated strategy of association mapping, QTL analysis, candidate gene and haplotype analysis was utilized to elucidate the complex genetic architecture of HSW in a panel of diverse soybean cultivars. Our study revealed 22 SNPs significantly associated with HSW through association mapping using five GWAS models across multiple environments plus a combined environment. By considering the detection of SNPs in multiple environments and GWAS models, the genomic regions of eight consistent SNPs within the ± 213.5kb were depicted as stable QTLs. Among the eight QTLs, four, viz. qGW1.1, qGW1.2, qGW9 and qGW16, are reported here for the first time, and the other four, viz. qGW4, qGW8, qGW17 and qGW19, have been reported in previous studies. Thirty-two genes were detected as putative candidates within physical intervals of eight QTLs by in silico analysis. Twelve genes (out of total 32) showed significant differential expression patterns among the soybean accessions with contrasting HSW. Moreover, different haplotype alleles of 10 candidate genes are associated with different phenotypes of HSW. The outcome of the current investigation can be used in soybean breeding programs for producing cultivars with higher yields.

Identification of genes associated with zinc and copper concentrations in walnut (Juglans regia L.) by GWAS analysis

Identification of genes associated with zinc and copper concentrations in walnut (Juglans regia L.) by GWAS analysis

Advancing Statistical Methodologies for Composite Phenotype Analysis in Genome-Wide Association Studies

Genome wide association studies (GWAs) have revolutionized our understanding of the genetic basis of complex traits by linking specific genetic variants to phenotypes. However, the analysis of composite phenotypes derived from multiple interrelated variables presents unique challenges, particularly in maintaining statistical power and interpretability. Conventional approaches often analyze each trait independently at a single time point, potentially neglecting the underlying correlations and developmental dynamics across different growth stages, which could significantly enhance the detection power of genetic associations. This study presents a novel statistical approach that combines phenotypic data from different plant developmental stages using a compressed linear mixed model (CLMM) to efficiently link the genotypes to phenotypes. The CLMM offers computational efficiency by leveraging dimensionality reduction and data compression techniques, making it suitable for analyzing large-scale GWAs datasets. This capability is crucial given the rapidly growing volume of genomic data. The data used in this study was obtained from Leibniz Institute of Plant Genetics and Crop Plant Research (IPK)-Gatersleben, Germany, database. It includes maize phenomic data and 50K SNPs data for 262 maize inbred lines. The modelling was done in R-statistical software following the guidelines of the Gapit tool. Plant growth was assessed at three time points: 11, 26 and 42 days after sowing (DAS). The models were compared using Akaike Information Criterion (AIC) and Information Criterion (BIC). The results showed that the model based incorporating plant volume, plant height, and plant surface area provided a better fit to the data compared to the models based on plant volume and plant surface area or plant height and plant volume. This is evidenced by lower AIC value of 1967.630 and BIC value of 1999.870 for the model incorporating three phenotypic traits (plant volume, Height and Surface area), compared to the AIC of 2008.560 and BIC of 2040.795 and AIC of 2312.930 for the model based on two phenotypic traits (plant volume and surface area) and BIC of 2351.321 for the for the model based on two phenotypic traits (plant height and volume). In the GWAs analysis, the results showed that the model incorporating three phenotypic traits (plan volume, height and area) detected the highest number of SNPs, with a total of 22 SNPs identified, compared to 11 SNPs detected using the model based on two phenotypic traits (plant surface area and volume) and 9 SNPs for the model based on two phenotypic traits (plant height and volume) across all growth stages considered. These findings suggest that combining traits to generate composite phenotypes in GWAS across different growth time points provides a robust framework that enhances the detection of genetic associations while preserving the biological relevance of the relationships between traits. This approach has significant implications for future GWAS, particularly in the study of complex traits, where understanding the interplay of multiple phenotypic variables is crucial for unraveling the genetic basis of complex traits.

Genome-Wide Association Study of Grape Texture Based on Puncture.

Grapes are grown extensively around the world and play a crucial role in overall fruit production globally. The quality of the grape is largely determined by the texture of the flesh, making it a key focus for grape breeders. Our study was conducted on 437 grape accessions using a puncture method to analyze berry texture characteristics. The results reveal strong correlations among the five texture parameters of grape accessions. Following the GWAS analysis using 2,124,668 population SNPs, 369 significant SNP locations linked to the grape berry texture were discovered. Through the process of gene annotation and expression analysis in the localization regions, several genes potentially linked to berry texture were identified, including E13A, FIS1A, CML35, AGL2, and AGL62. E13A, FIS1A, and CML35 were identified as potentially more relevant to grape berry texture based on gene expression analysis. Further investigation through transient transformation demonstrated that overexpressing E13A and CML35 resulted in notable changes in grape pulp texture. During this study, the berry textures of 437 grape accessions were comprehensively evaluated, and several important candidate genes were screened based on GWAS and analysis of gene function. This discovery paves the way for future research and breeding initiatives related to grape berry texture.

GWAS analysis for plant height and stem diameter in sorghum using multiple phenotyping approaches

AbstractSorghum (Sorghum bicolor (L.) Moench) is an important cereal crop cultivated around the globe. To identify the genomic regions responsible for plant height and stem diameter, a subset of the sorghum association panel was phenotyped using manual, ground‐robot, and drone‐based phenotyping approaches during 2019 and 2020 at Tifton, GA. Manual and ground‐robot‐based plant heights had a lower correlation (r = 0.55) than the manual and drone‐based measurements (r = 0.61). Tukey's mean difference plot analysis indicated that both high‐throughput methods were less accurate with taller accessions. In genome‐wide association studies using single nucleotide polymorphisms (SNPs), insertions and deletions (indels), and copy number variants, a total of 136 and 18 SNP loci associated with plant height were identified using mixed linear model and fixed and random model circulating probability unification models. For the first time, we report eight significant SNPs associated with stem diameter using a ground‐based robot. We were able to detect all four major dwarfing genes (Dw1 through Dw4) using manual phenotyping; in contrast, Dw2 was identified using both manual and ground‐robot‐based phenotyping. Sorbi.3004G093400, a gene located 19 kb upstream of the SNP locus SBI‐04_7987371 and a member of the glycoside hydrolase superfamily 35, plays a role in stem diameter, plant height, and is involved in cellular processes. Novel associations (eight for stem diameter), SNPs, and structural variants identified in this study can be used for manipulating plant height and stem diameter in sorghum.

Integration of GWAS and transcriptomic analyses reveal candidate genes for duck gonadal development during puberty onset

BackgroundPuberty onset signifies the beginning of sexual maturation and reproductive phase in poultry indeed, and plays an essential role in genetics and breeding. Studying gonadal development is one of the important approaches to exploring the genetic mechanism of puberty onset.ResultIn our study, the phenotype data of the testes and ovaries of the 120-day-old Nonghua duck showed a large coefficient of variation, indicating that their gonads were in different developmental states. The CNV-based GWAS results for 358 Nonghua ducks showed two deleted-type CNVRs were associated with testicular weight (TW) and testicular percentage (TP), namely CNVR492 (Chr2: 59473501–59478500 bp) and CNVR494 (Chr2: 59514001–59517000 bp). Additionally, two both-type CNVRs were associated with ovarian weight (OW) and ovarian percentage (OP), namely CNVR557 (Chr2: 99951001–99956500 bp) and CNVR891 (Chr7: 39115001–39122500 bp). RNA-seq analysis showed 6228 and 1070 differentially expressed genes (DEGs) related to the TW and OW. These DEGs were mainly enriched in the MAPK signaling pathway, cytokine-cytokine receptor interaction, and focal adhesion, which were reported to affect gonadal development. Further, by joint analysis of CNV-based GWAS and RNA-seq data, 3 genes, including LOC106019197, CDH19 (LOC101793040), and TYW5 were identified as potential candidate genes for TW and OW. LOC106019197 and CDH19 were down-regulated in the heavier-testes group (> 5 g), while TYW5 was also down-regulated in the heavier-ovaries group (> 3 g). The qRT-PCR revealed that LOC106019197 and CDH19 exhibited higher expression levels in the wild/CN0 and CN0/CN0 genotypes compared to the wild/wild genotype. TYW5 showed the highest expression level in the wild/CN0 genotype and the lowest in the CN2/CN2 genotype. In addition, the expression levels of LOC106019197 and CDH19 were significantly higher at 0w than at 8w and 24w.ConclusionOur results revealed that LOC106019197 and CDH19 may act as inhibitors of duck testicular development. TYW5 may play a role in delaying ovarian development. These findings provide new insights into the mechanism of puberty onset in ducks.

Genome-wide association insights into the genomic regions controlling vegetative and oil production traits in Acrocomia aculeata

BackgroundMacauba (Acrocomia aculeata) is a non-domesticated neotropical palm that has been attracting attention for economic use due to its great potential for oil production comparable to the commercially used oil palm (Elaeis guineensis). The discovery of associations between quantitative trait loci and economically important traits represents an advance toward understanding its genetic architecture and can contribute to accelerating macauba domestication. Pursuing this advance, this study performs single-trait and multi-trait GWAS models to identify candidate genes associated with vegetative and oil production traits in macauba. Eighteen phenotypic traits were evaluated from 201 palms within a native population. Genotyping was performed with SNP markers, following the protocol of genotyping-by-sequencing. Given that macauba lacks a reference genome, SNP calling was performed using three different strategies: using i) de novo sequencing, ii) the Elaeis guineenses Jacq. reference genome and iii) the macauba transcriptome sequences. After quality control, we identified a total of 27,410 SNPs in 153 individuals for the de novo genotypic dataset, 10,444 SNPs in 158 individuals using the oil palm genotypic dataset, and 4,329 SNPs in 167 individuals using the transcriptome genotypic dataset. The GWAS analysis was then performed on these three genotypic datasets.ResultsStatistical phenotypic analyses revealed significant differences across all studied traits, with heritability values ranging from 63 to 95%. This indicates that the population contains promising genotypes for selection and the initiation of breeding programs. Genetic correlations between the 18 traits ranged from -0.47 to 0.99. The total number of significant SNPs in the single-trait and multi-trait GWAS was 92 and 6 using the de novo genotypic dataset, 19 and 11 using the oil palm genotypic dataset, and 1 and 2 using the transcriptome genotypic dataset, respectively. Gene annotation identified 12 candidate genes in the single-trait GWAS and four in the multi-trait GWAS, across the 18 phenotypic traits studied, in the three genotypic datasets. Gene mapping of the macauba candidate genes revealed similarities with Elaeis guineensis and Phoenix dactylifera. The candidate genes detected are responsible for metal ion binding and transport, protein transportation, DNA repair, and other cell regulation biological processes.ConclusionsWe provide new insights into genomic regions that map candidate genes associated with vegetative and oil production traits in macauba. These potential candidate genes require confirmation through targeted functional analyses in the future, and multi-trait associations need to be scrutinized to investigate the presence of pleiotropic or linked genes. Markers linked to traits of interest could serve as valuable resources for the development of marker-assisted selection in macauba for its domestication and pre-breeding.

Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma

Primary open-angle glaucoma typically presents as two subtypes. This study aimed to elucidate the shared and distinct genetic architectures of normal-tension (NTG) and high-tension glaucoma (HTG), motivated by the need to develop intraocular pressure (IOP)-independent drug targets for the disease. We conducted a comprehensive multi-ethnic meta-analysis, prioritized variants based on functional annotation, and explored drug-gene interactions. We further assessed the genetic overlap between NTG and HTG using pairwise GWAS analysis. We identified 22 risk loci associated with NTG, 17 of which have not previously been reported for NTG. Two loci, BMP4 and TBKBP1, have not previously been associated with glaucoma at the genome-wide significance level. Our results indicate that while there is a significant overlap in risk loci between tension subtypes, the magnitude of the effect tends to be lower in NTG compared to HTG, particularly for IOP-related loci. Additionally, we identified a potential role for biologic immunomodulatory treatments as neuroprotective agents.

Shared genetic architecture between COVID-19 and irritable bowel syndrome: a large-scale genome-wide cross-trait analysis.

It has been reported that COVID-19 patients have an increased risk of developing IBS; however, the underlying genetic mechanisms of these associations remain largely unknown. The aim of this study was to investigate potential shared SNPs, genes, proteins, and biological pathways between COVID-19 and IBS by assessing pairwise genetic correlations and cross-trait genetic analysis. We assessed the genetic correlation between three COVID-19 phenotypes and IBS using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Two different sources of IBS data were combined using METAL, and the Multi-trait analysis of GWAS (MTAG) method was applied for multi-trait analysis to enhance statistical robustness and discover new genetic associations. Independent risk loci were examined using genome-wide complex trait analysis (GCTA)-conditional and joint analysis (COJO), multi-marker analysis of genomic annotation (MAGMA), and functional mapping and annotation (FUMA), integrating various QTL information and methods to further identify risk genes and proteins. Gene set variation analysis (GSVA) was employed to compute pleiotropic gene scores, and combined with immune infiltration algorithms, IBS patients were categorized into high and low immune infiltration groups. We found a positive genetic correlation between COVID-19 infection, COVID-19 hospitalization, and IBS. Subsequent multi-trait analysis identified nine significantly associated genomic loci. Among these, eight genetic variants were closely related to the comorbidity of IBS and COVID-19. The study also highlighted four genes and 231 proteins associated with the susceptibility to IBS identified through various analytical strategies and a stratification approach for IBS risk populations. Our study reveals a shared genetic architecture between these two diseases, providing new insights into potential biological mechanisms and laying the groundwork for more effective interventions.

A genome-wide cross-trait analysis identifying shared genetic basis and causal relationships between Hunner-type interstitial cystitis and autoimmune diseases in East Asian populations.

Epidemiological studies have demonstrated the clinical link between Hunner interstitial cystitis (HIC) and autoimmune diseases (ADs), suggesting potential shared genetic bases for their comorbidity. We aimed to investigate the shared genetic architecture and causal relationships between HIC and ADs. We conducted a genome-wide cross-trait study with ~170000 individuals of East Asian ancestry to investigate the shared architecture between HIC and ADs. Bidirectional Mendelian randomization (MR) was used to assess potential causal relationships and a multi-trait analysis of GWAS (MTAG) was conducted to identify their associated pleiotropic loci. Fine-mapping analysis narrowed candidate gene susceptibility loci and colocalization analysis was performed to identify shared variants at specific locus. Lastly, transcriptome-wide association (TWAS) and functional analysis were utilized to explore potential shared gene-tissue associations. Through bidirectional MR analysis, we observed a positive causal effect of AIH(ORIVW=1.09, PIVW=1.00×10-3) and RA (ORIVW=1.47, PIVW<1.00×10-4) on HIC and a negative causal effect of UC on HIC (ORIVW=0.89, PIVW< 1.00×10-4). Furthermore, we unveiled a robust positive causal effect of HIC on T1D(ORConMix=1.05, PConMix=1.77×10-3). Cross-trait meta-analysis identified a total of 64 independent SNPs associated with HIC and ADs. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the autoimmune system. Our findings might offer insights into the shared underlying etiology of HIC and ADs.

EPID-19. INTERACTION BETWEEN GERMLINE AND SOMATIC GENETICS TO ELUCIDATE RISK OF ADULT DIFFUSE GLIOMA

Abstract Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.