Susceptibility Loci Research Articles

Linking Iris Cis-Regulatory Variants to Primary Angle-Closure Glaucoma Via Clinical Imaging and Multiomics.

To elucidate the genetic basis of primary angle-closure glaucoma (PACG) by identifying pathogenic tissue and critical tissue-specific variants. The correlations among PACG susceptibility, axial length (AL), and anterior chamber depth (ACD) were evaluated using meta-analyses. Propensity score matching was utilized on 2161 participants from the Handan Eye Study to determine the risk factors independent of ACD and AL for PACG. Subsequently, we employed the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to screen 202 PACG genome-wide association study (GWAS) variants for chromatin accessibility and functional roles. The meta-analysis found that PACG susceptibility loci are not associated with ACD or AL. However, abnormal iris phenotypes emerged as significant independent risk factors for primary angle-closure disease (PACD), unrelated to ACD and AL. Substantial enrichment of PACG heritability was observed in the open chromatin regions of the human iris. Within the iris-relevant cellular context, 22 out of the 202 PACG GWAS variants could influence enhancer activity. Two variants in the iris open chromatin regions were implicated in the modulation of PLEKHA7 and C10orf53 expression. The downregulation of these two genes affects cytoskeletal organization. Our findings underscore the importance of the iris in the pathogenesis of PACG and identified iris-specific, enhancer-modulating variants that may influence disease risk. Our approach also provides a generalizable framework for studying ocular diseases from the perspective of enhancer-modulating variants.

Identification of Genetic Factors Related With Nonhereditary Colorectal Polyposis and Its Recurrence Through Genome-Wide Association Study.

Many patients with colorectal polyposis demonstrate negative results in germline mutation test. This study aimed to uncover genetic variants associated with nonhereditary colorectal polyposis using a genome-wide association study (GWAS). At a single referral university hospital, between January 2012 and September 2021, 638 patients with ≥ 10 biopsy-proven cumulative polyps on colonoscopy without germline mutations related to hereditary colorectal cancer or polyposis were included. The control group comprised 1863 individuals from the Korea Medical Institute, each having undergone at least two colonoscopies, all of which were normal. This study utilized GWAS to identify susceptibility loci for nonhereditary colorectal polyposis. Genetic differences between patients with and without ≥ 10 polyp recurrences were analyzed using Cox proportional hazards models. GWAS revealed 71 novel risk single-nucleotide polymorphisms (SNPs) not seen in previous colorectal cancer and polyp GWAS. Five genes (UPF3A, BICRA, CBWD6, PDE4DIP, and ABCC4) overlapping seven SNPs (rs566295755, rs2770288, rs1012003, rs201270202, rs71264659, rs1699813, and rs149368557), previously linked to colorectal cancer, were identified as significant risk factors for nonhereditary colorectal polyposis. Two novel genes (CNTN4 and CNTNAP3B), not previously associated with colorectal diseases, were identified. Three SNPs (rs149368557, rs12438834, and rs9707935) were significantly associated with higher risk of recurrence of polyposis. The gene overlapping with rs149368557 was ABCC4, which was also significantly associated with an increased risk of nonhereditary colorectal polyposis. This study identified 71 novel risk variants for nonhereditary colorectal polyposis, with three SNPs (rs149368557, rs12438834, and rs9707935) indicating significant associations with increased risk of polyposis recurrence.

A genome-wide meta-analysis reveals shared and population-specific variants for allergic sensitization.

Allergic diseases are major causes of morbidity in both developed and developing countries and represent a global burden on health care systems. Allergic sensitization is defined as the production of immunoglobulin E (IgE) specific to common environmental allergens, and it is an important indicator in the assessment of allergic diseases. This study aimed to clarify the genetic basis of allergic sensitization. We performed a genome-wide association study (GWAS) of allergic sensitization in the Japanese population, followed by a cross-ancestry meta-analysis with a European population, involving a total of 20,492 cases and 23,342 controls for Japanese and 8,246 cases and 16,786 controls for Europeans. We also performed a polysensitization GWAS of a Japanese population involving 4,923 cases and 17,009 controls. A total of 18 susceptibility loci for Japanese only and 23 allergic sensitization loci for the cross-ancestry population were identified by GWAS, among which 4 loci were novel. We also identified 8 GWAS significant loci for polysensitization. Expression quantitative trait locus colocalization analysis revealed polysensitization GWAS significant variants affecting both the phenotype and expression of the CD28, LPP, and LRCC32 genes. Cross-population genetic correlation analysis of allergic sensitization suggested that heterogeneity exists in allergic sensitization between Europeans and Japanese, indicating that more genetic heterogeneity may exist in allergic sensitization than allergic diseases. Our investigation provided new insights into the molecular mechanism of allergic sensitization that could enhance current understanding of allergy and allergic diseases.

Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III region

This study aims to confirm the associations of air pollution with ulcerative colitis (UC) and Crohn's disease (CD); to explore interactions with genetics and lifestyle; and to characterize potential epigenetic mechanisms. We identified over 450,000 individuals from the UK Biobank and investigated the relationship between air pollution and incident inflammatory bowel disease (IBD). Cox regression was utilized to calculate hazard ratios (HRs), while also exploring potential interactions with genetics and lifestyle factors. Additionally, we conducted epigenetic Mendelian randomization (MR) analyses to examine the association between air pollution-related DNA methylation and UC. Finally, our findings were validated through genome-wide DNA methylation analysis of UC, as well as co-localization and gene expression analyses. Higher exposures to NOx (HR=1.20, 95% CI 1.05-1.38), NO2 (HR=1.19, 95% CI=1.03-1.36), PM2.5 (HR=1.19, 95% CI=1.05-1.36) and combined air pollution score (HR=1.26, 95% CI=1.11-1.45) were associated with incident UC but not CD. Interactions with genetic risk score and lifestyle were observed. In MR analysis, we found five and 22 methylated CpG sites related to PM2.5 and NO2 exposure to be significantly associated with UC. DNA methylation alterations at CXCR2 and sites within the MHC class III region, were validated in genome-wide DNA methylation analysis, co-localization analysis and analysis of colonic tissue. We report a potential causal association between air pollution and UC, modified by lifestyle and genetic influences. Biological pathways implicated include epigenetic alterations in key genetic loci, including CXCR2 and susceptible loci within MHC class III region. Xue Li was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (No. 82204019). ET was supported by the CRUK Career Development Fellowship (C31250/A22804) and the Research Foundation Flanders (FWO). JW was supported by Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). JKN was supported by the National Science Center, Poland (No. 2020/39/D/NZ5/02720). The IBD Character was supported by the European Union's Seventh Framework Programme [FP7] grant IBD Character (No. 2858546).

Exome sequencing of Singapore Chinese anti-citrullinated-protein-antibody-positive rheumatoid arthritis patients.

More than 130 susceptibility loci for rheumatoid arthritis (RA) have been identified with genome-wide association studies (GWAS). To investigate the genetic predisposition of Chinese anti-cyclic-citrullinated-peptides-antibody-positive RA, we carried out an exome sequencing study. Patients were recruited from three major public hospitals in Singapore, Tan Tock Seng Hospital (TTSH), Singapore General Hospital and National University Health System. Controls came from an established exome collection and from the TTSH Health Control Biobank. All the participants were of Chinese descent. We performed whole-exome sequencing (WES) in 595 ACPA-positive RA patients and 1281 controls and validated the candidate variants by genotyping 795 RA cases and 600 controls. The discovery cohort yielded 73 susceptibility SNVs that reached statistical significance. In the validation study with an independent cohort, two SNVs remained significant: PCNXL4 (p-value 1.50x10-5) and DHRS7 (p-value 6.02x10 -5). The majority of known susceptibility foci are not captured by exome sequencing. In this WES study of ACPA-positive RA in Chinese patients, we discovered two new variants in PCNXL4 and DHRS7 associated with risk of the disease.

Functional and Practical Insights Into the Genetic Basis of Takayasu Arteritis.

Takayasu arteritis (TAK) is a rare vasculitis characterized by inflammation of large arteries. Although the exact etiology of TAK remains unclear, a genetic predisposition to the disease has been established. Large-scale genetic studies have significantly contributed to the identification of genetic variation associated with immune-mediated diseases. To date, five genome-wide association studies (GWAS) have been performed in TAK, identifying multiple genetic susceptibility loci across the genome. Here, we summarize the major findings from GWAS in TAK and provide an in silico functional evaluation of the associated loci (P < 5 × 10-8) and variants in high linkage disequilibrium with them (r2 > 0.8). By exploring gene expression and chromatin interaction data, we identified candidate causal genes in TAK, some of them with well-known functional implications. The analysis of transcription factor motifs within TAK-associated loci revealed enrichment of the STAT and RUNX families, both characterized by their role in immune functions and inflammatory responses. The enrichment in biological processes in susceptibility loci confirmed the involvement of specific immune-related pathways in TAK. Further, we devised and calculated a cumulative genetic risk score for TAK and confirmed differences in genetic risk for the disease among ancestries. Finally, we provide a practical guide to communicate genetic information for TAK to patients and families.

CCN3/NOV as a potential therapeutic target for diverticular disease: A proteome-wide Mendelian randomization study.

Genome-wide association studies (GWAS) identified over 100 susceptibility loci and candidate causal genes for diverticular disease (DD) at the transcriptional level. However, effective therapeutics or preventions based on underlying disease mechanisms remain to be elucidated. In this study, we explored potential causal genes for DD at the protein level. We used 2 GWAS summary statistics of DD; 1 was obtained from the United Kingdom Biobank (UKBB) with 31,917 cases and 419,135 controls, and the other from the FinnGen consortium with 30,649 cases and 301,931 controls. For the primary analysis, we employed proteome-wide Mendelian randomization (MR) studies using 738 cis-acting protein quantitative trait loci (pQTLs) for 735 plasma proteins from the 5 published studies. For external validation, we conducted 2-sample MR analyses using plasma pQTLs of the screened proteins from another study by deCODE genetics. Moreover, we performed a series of sensitivity analyses including reverse MR and Bayesian colocalization tests. The primary MR identified 4 plasma proteins that were associated with DD risk including CCN3/NOV (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99; P = 1.2 × 10-11 for UKBB. OR, 0.73; 95% CI, 0.66-0.81; P = 7.2 × 10-10 for FinnGen). The validation MR well replicated the primary result of CCN3/NOV (OR, 0.95; 95% CI, 0.93-0.96; P = 1.9 × 10-11 for UKBB. OR, 0.43; 95% CI, 0.33-0.56; P = 7.0 × 10-10 for FinnGen). Sensitivity analyses supported the causal association. We prioritized plasma CCN3/NOV protein as a protective factor for DD for follow-up functional studies to elucidate the disease mechanisms and therapeutics.

A polygenic risk score model for psoriasis based on the protein interactions of psoriasis susceptibility loci.

Polygenic Risk Scores (PRS) are an emerging tool for predicting an individual's genetic risk to a complex trait. Several methods have been proposed to construct and calculate these scores. Here, we develop a biologically driven PRS using the UK BioBank cohort through validated protein interactions (PPI) and network construction for psoriasis, incorporating variants mapped to the interacting genes of 14 psoriasis susceptibility (PSORS) loci, as identified from previous genetic linkage studies. We constructed the PPI network via the implementation of two major meta-databases of protein interactions, and identified variants mapped to the identified PSORS-interacting genes. We selected only European unrelated participants including individuals with psoriasis and randomly selected healthy controls using an at least 1:4 ratio to maximize statistical power. We next compared our PPI-PRS model to (i) clinical risk models and (ii) conventional PRS calculations through p-value thresholding. Our PPI-PRS model provides comparable results to both clinical risk models and conventional approaches, despite the incorporation of a limited number of variants which have not necessarily reached genome-wide significance (GWS). Exclusion of variants mapped to the HLA-C locus, an established risk locus for psoriasis resulted in highly similar associations compared to our primary model, indicating the contribution of the genetic variability mapped to non-GWS variants in PRS computations. Our findings support the implementation of biologically driven approaches in PRS calculations in psoriasis, highlighting their potential clinical utility in risk assessment and treatment management.

Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci

Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.

Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-Related Macular Degeneration

To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia. A genome-wide association study (GWAS) meta-analysis (meta-GWAS). We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV. We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. The association between SNPs and mMNV in patients with high myopia. The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]meta = 0.62, Pmeta = 4.63 × 10-8, I2 = 0.00), which was consistently associated with mMNV in all datasets (ORASA = 0.59, PASA = 1.71 × 10-4; OR610K = 0.63, P610K = 5.53 × 10-4; ORWGS = 0.66, PWGS = 4.38 × 10-2). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORmeta = 0.52, Pmeta = 1.55 × 10-5), while rs61871745 near ARMS2 showed a marginal association (ORmeta = 1.25, Pmeta =7.79 × 10-3). Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.

Genome-wide Association Studies of Diabetic Kidney Disease in East Asians With Type 2 Diabetes: Achievements and Future Perspectives.

Diabetic kidney disease is a devastating diabetic complication, affecting up to half of people suffering from diabetes. The global burden of diabetic kidney disease is steadily increasing worldwide along with the growing prevalence of type 2 diabetes. The epidemic rise of type 2 diabetes is primarily observed in Asia, including the East Asian regions. It is generally accepted that heredity is one of the main determinants in the pathogenesis of diabetic kidney disease. Since the advent of genome-wide association studies, numerous studies have been published to identify the genetic loci susceptible to diabetic kidney disease among diverse populations. Although genome-wide association studies exploring diabetic kidney disease susceptibility loci have focused primarily on populations of European descent, a number of novel genetic variants associated with diabetic kidney disease have also been successfully revealed among East Asians. A comprehensive analysis of the genetic architecture and pathophysiological pathways of diabetic kidney disease may allow the identification of new potential therapeutic targets. This review aimed to summarize genome-wide association studies examining genetic variants associated with diabetic kidney disease in the populations of East Asian ancestry with type 2 diabetes and presented our perspective on the future of this field.

Role of common variants and new genes associated with arrhythmogenic cardiomyopathy

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease, predominantly affecting males, characterized by fibro-fatty myocardial replacement mainly in the right ventricle. It leads to 5% sudden cardiac death in affected young adults (&amp;lt;25 yo) without an implantable cardioverter defibrillator. Early diagnosis is crucial for appropriate clinical management to reduce mortality and prevent disease progression. Rare variants in desmosomal genes (PKP2,DSC2,DSG2,DSP and JUP) are found in 50% of cases. However, challenges persist since we observe a low penetrance in relatives (28-58%) and a high variability in expressivity and severity annihilating any preventive strategy. Objective We aim to decipher the genetic architecture of ACM by investigating the role of common variants in disease susceptibility/severity and to idendify new genes associated to ACM. Method A Genome Wide Association Study (GWAS) was performed on 1079 ACM index patients and 7305 controls, followed by conditional analysis. New candidate genes were knocked out (KO) in Zebrafish and/or hiPSC using CRISPR/Cas9. Impedance and external field potential measurements were performed on hiPSC derived cardiomyocytes (CM-hiPSC). Results The GWAS identified 5 significant loci (Figure 1, P&amp;lt;5.10-8), including 2 desmosomal genes (PKP2 a n d DSG2) and 3 new candidates (KLF12, CTNNA3, and ARL17B/WNT3). Conditional analysis revealed 3 additional loci with suggestive p-values (P&amp;lt;1.10-6), highlighting 3 new susceptible loci. Among them, we uncovered key non-coding regulatory regions near desmosomal genes (DSC2 and DSG2). Initial findings in PKP2-KO zebrafish present hearts with structural defects, while CM-hiPS KLF12-KO(-/-) exhibited altered interbeat interval and relaxation time compared to isogenic controls. Conclusion Our findings reveal ACM's complex genetic architecture, implicating common variants in disease susceptibility. A polygenic risk score will be implemented to improve patient risk stratification. Three novel loci/genes for ACM as well as specific regulatory regions of desmosomal genes have been highlighted. Their functional studies in isogenic hiPSC and Zebrafish models will offer new insights in ACM underlying molecular mechanism and potential therapeutic targets.

Micro-capture-C in vessel wall cell types identifies mechanisms underlying coronary artery disease susceptibility loci

Abstract Genetics is estimated to account for 50% of Coronary Artery Disease (CAD) risk. Genome-Wide Association Studies (GWAS) have revealed 100s of genomic loci which are associated with CAD (1). However, moving from GWAS signals to causal genes has proved challenging, slowing progress in developing interventions for CAD and other diseases. The greatest challenge in interpreting GWAS data is that only 10% of variants are in protein-coding regions and 90% are in "non-coding" genomic regions. Many of these non-coding variants are found in regulatory elements such as enhancers. Enhancers are distal regulatory elements that bind transcription factors and regulate genes up to 1 million base pairs away. This is achieved by DNA looping bringing enhancers into physical proximity with target genes. However, it is not possible to predict which gene(s) a given enhancer will regulate based on genomic location alone. We aimed to develop a generalisable workflow to solve CAD GWAS signals accurately and sensitively, by identifying causal enhancer SNPs and linking them mechanistically to output genes in a cell-type specific manner. We combined cell-specific epigenomic mapping with machine learning to prioritise 21,959 SNPs from 861 candidate CAD loci, in endothelial cells (HUVECs) and smooth muscle cells (HCASMCs). Micro-Capture-C (MCC) was used to resolve enhancer-promoter interactions at base-pair resolution (2). MNase footprinting determined differential transcription factor binding at specific enhancer SNPs. In HCASMCs, 20 putative enhancers containing CAD SNPs were found to interact with 32 genes, and in HUVECs 25 enhancers interacted with 48 genes. These genes were enriched for pathways including TGFb signalling, RUNX3 activity, and MAPK6/MAPK4 signalling. To prove causality at specific loci, heterozygous SNPs were identified in the individual primary cell lines. The interaction frequency at these elements was statistically compared between risk and non-risk alleles. For example, at the 9p21.3 locus, an enhancer containing a non-risk T allele was found to interact more strongly with the CDKN2B gene, compared to the risk G allele. Interestingly, this imbalance between allele interaction was potentiated by stimulation with TGFb, a key mediator in atherosclerosis. Furthermore, the transcription factor footprint at the SNP location was altered by the risk allele, indicating the mechanistic cause of the CAD-associated change in CDKN2B expression. We demonstrate a combined computational and experimental approach to identify causal non-coding variants in CAD risk loci, at scale. Among the key outputs of this study is the identification of the risk variant (rs1537373), output gene (CDKN2B), and specific cell type (HCASMC) underlying the 9p21.3 locus association with CAD risk. Using this approach to translate GWAS signals into cell-type specific outputs genes, will lead to a better understanding of the pathogenesis of CAD, and new therapeutic opportunities.

Investigating the role of WT1 in Brugada syndrome pathophysiology

Abstract Background Brugada syndrome (BrS) is a heritable arrhythmic disorder presumably caused by conduction slowing in the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study found an association between common variants on chromosome 11 near WT1, tagged by the SNP rs72905083, and BrS susceptibility. Purpose To study whether WT1 affects cardiac conduction and could therefore represents the underlying association of the chr11 locus with BrS susceptibility. Methods We conducted in silico analyses of omics datasets to identify the likely causal gene at the chr11 BrS locus. Next, we conducted electrophysiological studies in heterozygous young adult (4 months old) Wt1-deficient (Wt1+/-) mice and wild-type littermates to explore the effect of Wt1 on cardiac conduction. To study the potential role of Wt1 in the setting of reduced conduction reserve, we compared aged Scn5a haploinsufficient mice (Scn5a+/-;Wt1+/+, 17 months) with littermates haploinsufficient for both Wt1 and Scn5a (Scn5a+/-;Wt1+/-). Optical mapping was performed in Langendorff-perfused hearts, where conduction was further challenged by acute ajmaline administration or by pacing at the effective refractory period (ERP). Transcriptomic analyses were conducted in Wt1+/- and wild-type mice by RNAseq of PCM1-sorted cardiomyocytes. Results Analysis of omics datasets uncovered WT1 as the likely causal gene since WT1 was the closest gene to, and in fact overlapped, the BrS-associated region; promoter capture Hi-C data in human tissue showed chromatin contact between the promoter of WT1 and the associated region; and H3K27ac ChIP-seq signals (i.e. enhancer activity) of putative cardiac enhancers located within the associated region were correlated with WT1 transcript abundance across multiple tissues (Z-score = 4.32, p=1.57e-05). No differences were observed in ECG parameters or optically mapped epicardial conduction between Wt1+/- mice and wild-type littermates. However, comparison of aged Scn5a+/-;Wt1+/- and Scn5a+/-; Wt1+/+ hearts, in the setting of acute ajmaline challenge or pacing at the ERP, showed faster conduction in RV/RVOT in the presence of Wt1 haploinsufficiency (genotype effect: p=0.057 and p=0.041 for RV and RVOT epicardial conduction, respectively, during ajmaline challenge; p=0.034 for RV epicardial conduction during pacing at ERP). RNAseq of RV/RVOT cardiomyocytes revealed higher Scn5a expression in Wt1+/- vs wild-type (p=0.006). Conclusion We identified WT1 as the gene that most likely underlies the effect of the chr11 BrS susceptibility locus. Functional data revealed protective effects of reduced Wt1 expression in the setting of reduced conduction reserve. Transcriptomic data suggest that this occurs through a transcriptional effect on Scn5a expression.

Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immune system, playing a major role in orchestrating innate and adaptive immune responses. Both Alzheimer's disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are enriched for genes expressed in myeloid cells, but it is not clear whether these myeloid risk factors are shared between the two diseases. Leveraging results of genome-wide association studies, we investigated the causal effect of IBD (including ulcerative colitis (UC) and Crohn's disease (CD)) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed distinct sets of genes and pathways of AD and IBD susceptibility loci. Specifically, AD loci are enriched for microglial eQTLs, while IBD loci are enriched for monocyte eQTLs. However, we also found that genetically determined IBD is associated with a protective effect against AD (p<0.03). Yet, a genetic propensity for the CD subtype is associated with increased amyloid accumulation (beta=7.14, p-value=0.02) and susceptibility to AD. Susceptibility to UC was associated with increased deposition of TDP-43 (beta=7.58, p-value=6.11×10-4). The relation of these gastrointestinal inflammatory disease to AD is therefore complex; while the different subsets of susceptibility variants preferentially affect different myeloid cell subtypes, there do appear to be certain shared pathways and the possible protective effect of IBD susceptibility on the risk of AD which may provide therapeutic insights.

FAM13A polymorphism is associated with a usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease.

The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis (RA)-related interstitial lung disease (ILD), but not with systemic sclerosis (SSc)-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general. We performed a cross-sectional study of SSc-ILD patients from 4 US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate, or alternative diagnosis, according to American Thoracic Society criteria. Four-hundred eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying 2 copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (OR 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (OR 3.65, 95% CI 1.25-10.65). We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.

Dietary glutamine supplementation improves both Th1 and Th17 responses via CARD11-mTORC1 pathway in murine model of atopic dermatitis

Glutamine (GLN) is considered an immunomodulatory nutrient, while caspase recruitment domain 11 (CARD11) is a susceptibility locus for atopic dermatitis (AD). T-cell antigen receptor (TCR)-stimulated GLN uptake requires CARD11. However, the specific pathogenesis of AD via GLN uptake remains unclear. This study aimed to elucidate the association between dietary GLN supplementation and the CARD11 pathway in the pathogenesis of AD, focusing on T helper type 1 (Th1) and Th17 cell expression in AD. Herein, wild-type (WT) mice with house dust mite epidermal-sensitized skin exhibited increased expression of interferon-gamma (IFN-gamma) and interleukin (IL)-17, whereas CARD11 deficiency impaired Th1 and Th17 responses at the same site. CARD11 is a key mediator of Th1 and Th17 expression in AD. Additionally, we suppressed mammalian target of rapamycin complex 1 (mTORC1) signaling, downstream of CARD11, to underscore the critical role of CARD11 in mediating Th1 and Th17 expression in AD. Further, dietary supplementation of GLN to CARD11−/− mice restored Th1 and Th17 responses, whereas inflammatory expression was reduced in WT mice, and p-CARD11 expression and mTORC1 signaling activity were increased in JPM50.6 cells and CARD11−/− mice. Upon inhibiting the GLN transporter, alanine-serine-cysteine transporter carrier 2 (ASCT2), we observed that the Th1 and Th17 response in AD was reduced. Conclusively, ASCT2-mediated GLN uptake improves the expression of Th1 and Th17 cells via CARD11-mTORC1 signaling pathway in AD, suggesting the potential of glutamine supplementation for AD treatment.

Multi-ancestry GWAS meta-analyses of lung cancer reveal susceptibility loci and elucidate smoking-independent genetic risk

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits.

Colocalization of genetic regions that confer resistance/susceptibility against Puccinia species and association with Pyrenophora teres loci within the barley genome

Cereal rust diseases, including leaf, stem, and stripe rust, are some of the most devastating and economically important diseases of barley. However, host–pathogen genetic interaction research for each pathosystem is typically conducted independently and in isolation. Examples of host resistance/susceptibility genes functioning sympathetically to multiple pathogens or antagonistically to additional pathogens have been reported. Therefore, consolidation of loci that have been reported in multiple studies and across pathosystems is useful for variety development to maximize resistance to multiple pathogens and avoid inadvertent incorporation of susceptibility loci that act antagonistically to other pathogens. This review summarizes loci reported in three key biotrophic pathosystems of barley, including leaf, stem, and stripe rust. In conjunction with previously consolidated net blotch loci, this review lays the foundation for a wider barley rust resistance/susceptibility atlas. This review aims to inform breeders and researchers in rapidly identifying accessions and loci that need further characterization and which loci would be most useful to introgress into elite varieties.

Using a Polygenic Risk Score to Improve the Risk Prediction of Non-Small Cell Lung Cancer in Taiwan.

Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs. We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al. We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778. The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.