Genome-wide Association Study Of Susceptibility Research Articles

A novel locus in CSMD1 gene is associated with increased susceptibility to severe malaria in Malian children

BackgroundPlasmodium falciparum malaria is still a leading cause of child mortality in sub-Saharan Africa. The clinical manifestations of malaria range from asymptomatic infection to severe disease. The variation in clinical presentation is partly attributed to host genetic factors with estimated narrow-sense heritability of 23%. Here, we investigate the associations between candidate gene polymorphisms and the likelihood of severe malaria (SM) in a cohort of Malian children.MethodsBased on our previous genome-wide association studies (GWAS) analysis, candidate genes were selected for in-depth analysis using several criteria including gene-level GWAS scores, functional overlap with malaria pathogenesis, and evidence of association with protection or susceptibility to other infectious or inflammatory diseases. Single Nucleotide Polymorphisms (SNPs) residing within these genes were selected mainly based on p-values from previous severe malaria susceptibility GWAS studies and minor allele frequency (MAF) in West African populations.ResultsOf 182 candidate genes reported in our previous study, 11 genes and 22 SNPs residing in these genes were selected. The selected SNPs were genotyped using KASP technology in 477 DNA samples (87 SM and 390 controls). Logistic regression analysis revealed that a common intron variant, rs13340578 in CUB and Sushi Multi Domain (CSMD1) gene, is associated with increased odds of SM in recessive mode of inheritance (MAF = 0.42, OR = 1.8, 95% CI = [1.78, 1.84], p = 0.029). The SNP is in linkage disequilibrium (LD) with multiple variants with regulatory features.ConclusionTaken together, the current study showed that an intron variant rs13340578, residing in CSMD1 gene, is associated with increased susceptibility to malaria. This finding suggests that modified regulation of complement may contribute to malaria disease severity. Further studies are needed to identify the causal variants and the underlying molecular mechanisms.

A genome-wide association study of susceptibility to upper urinary tract infections.

Our goal was to identify genetic and modifiable risk factors for upper urinary tract infections (UTIs). We used data from UK Biobank, The Trøndelag Health Study (HUNT), and Michigan Genomics Initiative (MGI) to conduct genome-wide association studies (GWASs) and sex-stratified analyses on upper UTI. Mendelian randomization (MR) analyses were conducted to examine potential causal relationships between cardiometabolic risk factors and upper UTIs. One genome-wide significant (P ≤ 5E-08) locus was associated with the susceptibility to upper UTI, located near TSN in the female-only analysis. Additionally, we identified suggestive (P ≤ 5E-06) loci near DNAI3 for the females, SCAMP1-AS1 for the males, and near TSN, LINC00603, and HLA-DQA2 for both sexes. In MR analyses, higher genetically predicted lifetime smoking scores were associated with an increased risk of developing upper UTI for females and both sexes (OR of 4.84, P = 4.50E-06 and OR of 2.79, P = 3.02E-05, respectively). We found that genetic variants near TSN was associated with the risk of upper UTIs among females. In addition, we found several genetic loci with suggestive associations with the risk of upper UTIs. Finally, MR analyses found smoking to be a potential causal risk factor for upper UTIs.

Genome-wide association study of susceptibility to hospitalised respiratory infections.

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P<5×10 -6, one of which was genome-wide significant ( P<5×10 -8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in Stage 2. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our Stage 1 analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate in the meta-analysis of Stages 1 and 2. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Genome-wide Association Study of Susceptibility to Respiratory Syncytial Virus Hospitalization in Young Children

Worldwide, respiratory syncytial virus (RSV) infections are among the most common causes of infant hospitalization. Host genetic factors influencing the risk and severity of RSV infection are not well known. We conducted a genome-wide association study (GWAS) to investigate single-nucleotide polymorphisms (SNPs) associated with severe RSV infections using a nested case-control design based on 2 Danish cohorts. We compared SNPs from 1786 children hospitalized with RSV to 45 060 controls without an RSV-coded hospitalization. We performed gene-based testing, tissue enrichment, gene-set enrichment, and a meta-analysis of the 2 cohorts. Finally, an analysis of potential associations between the severity of RSV infection and genetic markers was performed. We did not detect any significant genome-wide associations between SNPs and RSV infection or the severity of RSV. We did find potential loci associated with RSV infections on chromosome 5 in 1 cohort but failed to replicate any signals in both cohorts. Despite being the largest GWAS of severe RSV infection, we did not detect any genome-wide significant loci. This may be an indication of a lack of power or an absence of signal. Future studies might include mild illness and need to be larger to detect any significant associations.

Thyroid Function and COVID-19 Susceptibility and Its Severity: A Two-Sample Mendelian Randomization Study.

Several observational studies have confirmed the relationship between thyroid hormones and coronavirus disease 2019 (COVID-19), but this correlation remains controversial. We performed a two-sample Mendelian randomization (MR) analysis based on the largest publicly available summary datasets. Summary statistics with 49 269 individuals for free thyroxine (FT4) and 54 288 for thyroid stimulating hormone (TSH) were used as exposure instruments. Genome-wide association studies of susceptibility (cases = 38 984; controls = 1 644 784), hospitalization (cases: 9986 = controls = 1 877 672), and very severe disease (cases = 5101; controls = 1 383 241) of COVID-19 were used as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis, and utilized MR-Egger regression, weighted median, and robust adjusted profile score (RAPS) for sensitivity analysis. Genetic predisposition to higher serum levels of FT4 within the normal range was negatively associated with the risk of COVID-19 hospitalization (odds ratio [OR] = 0.818; 95% CI, 0.718-0.932; P = 2.6 × 10-3) and very severe disease (OR = 0.758; 95% CI, 0.626-0.923; P = 5.8 × 10-3), but not susceptibility. There is no evidence that genetically predicted circulating TSH levels are associated with COVID-19 susceptibility and severity risk. Neither apparent pleiotropy nor heterogeneity were detected in the sensitivity analysis. In summary, we found that higher FT4 levels may reduce the risk of COVID-19 severity, suggesting that thyroid function testing may be required for patients with COVID-19.

COVID-19 and risk of neurodegenerative disorders: A Mendelian randomization study

Emerging evidence has suggested a close correlation between COVID-19 and neurodegenerative disorders. However, whether there exists a causal association and the effect direction remains unknown. To examine the causative role of COVID-19 in the risk of neurodegenerative disorders, we estimated their genetic correlation, and then conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of susceptibility, hospitalization, and severity of COVID-19, as well as six major neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, multiple sclerosis, and Parkinson’s disease. We identified a significant and positive genetic correlation between hospitalization of COVID-19 and AD (genetic correlation: 0.23, P = 8.36E–07). Meanwhile, hospitalization of COVID-19 was significantly associated with a higher risk of AD (OR: 1.02, 95% CI: 1.01–1.03, P: 1.19E–03). Consistently, susceptibility (OR: 1.05, 95% CI: 1.01–1.09, P: 9.30E–03) and severity (OR: 1.01, 95% CI: 1.00–1.02, P: 0.012) of COVID-19 were nominally associated with higher risk of AD. The results were robust under all sensitivity analyses. These results demonstrated that COVID-19 could increase the risk of AD. Future development of preventive or therapeutic interventions could attach importance to this to alleviate the complications of COVID-19.

A genome-wide association study (GWAS) of event-free survival in follicular lymphoma treated in first-line therapy with immunochemotherapy: study design and initial results using a leave-one-cohort-out cross-validation statistical approach

Relatively few studies have evaluated the role of germline genetics in predicting outcome in FL and most of these were small candidate gene studies. In addition, adapting statistical designs used in susceptibility GWAS for outcomes is challenging. In fact, at the genome-wide scale, discoveries from one cohort may fail to replicate in other cohorts due to both cohort heterogeneity, the « winner curse » phenomenon, and limited statistical power. To identify robust and reproducible SNPs associated with event-free survival (EFS) of FL patients, we developed a specific cross-validation statistical design in a multi-cohort study in order to better balance statistical power across cohorts and identify robust findings that replicate across cohorts. We conducted a GWAS study of FL patients treated with immunochemotherapy for EFS with adjustment for population stratification using, FLIPI score, and use of rituximab maintenance. Cohorts were from prospective clinical trials of the Lymphoma Study Association (LYSA, PRIMA [N=391], RELEVANCE [N=396], the Fondazione Italiana Linfomi (FIL, FOL05, [N=199]) and the Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) (N=154), a prospective observational study. Genotyping for the GWAS was performed using Human Core exome (PRIMA, RELEVANCE, FOL05) and 660 Quad (SPORE) BeadChips (Illumina, San Diego, USA). Minimac4/1000G was used to impute additional SNPs. Statistical design is based on cross-validation statistical technique. Following a « leave-one-cohort-out » (LOCO) strategy, J train blocks are defined by combining iteratively the cohorts except cohort j which is left for validation purpose. A p-value threshold is defined to select the top SNPs from each train block, with subsequent validation based on p-value and hazard ratio estimate in the cohort that is left. Discordances between SNP hazard ratios from train and validation blocks indicates lack of reproducibility. At the end, SNPs are considered robust if they are discovered across several train blocks and validated with consistency. After standard quality control steps for genotyping, PCA for ancestry and population stratification (no exclusion) and imputation, 1,861,658 common SNPs for the five cohorts (N=1,140 patients) were analyzed. We will present in detail the cross-validation LOCO statistical design. Preliminary results for EFS indicated promising loci at chromosome 7 that replicated consistently across 4 out of the 5 train blocks in the unadjusted and adjusted Cox models. The LOCO design especially helps identifying SNPs with inconsistent results across cohorts. Some examples of divergent results across cohorts will be presented. The LOCO design can be used successfully to identify more robust results that are consistent across cohorts in GWAS, particularly in survival studies. Mots clés GWAS ; follicular lymphoma Déclaration de liens d'intérêts Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P&lt;5×10-6, one of which was genome-wide significant (P&lt;5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.

Background Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%–10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans.MethodsWe analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). ResultsSix loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10–6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42–0.66; P = 5.96 × 10−8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls.ConclusionsThis first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.

Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer.

The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09-1.36 and p = 0.0003], 0.82 (0.74-0.91 and p = 0.0002) and 1.21 (1.10-1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.

Identification of New Risk Loci and Regulatory Mechanisms Influencing Genetic Susceptibility to Acute Lymphoblastic Leukaemia

There is increasing evidence for an inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. In particular, genome-wide association studies (GWAS) have identified nine genomic regions with common polymorphisms associated with ALL risk. However, these loci cumulatively only explain a minority of the genetic risk of childhood ALL, and differences in the etiology amongst molelcular subtypes of ALL remain poorly understood. In this study, we performed one of the largest ALL susceptibility GWAS, totalling 5,321 cases and 16,666 controls of European descent, to comprehensively map ALL risk loci. With this large sample size, we also sought to identify risk genes for two major subtypes of ALL, namely those with ETV6-RUNX1 fusion and hyperdiploid ALL. This meta-analysis included four previously published GWAS datasets with European cases from the UK ALL cohorts and the German Berlin-Frankfurt-Münster ALL trials, and the US cases enrolled on ALL trials in Children's Oncology Group and at St. Jude Children's Research Hospital (Nat Genet2009, Blood 2012, Nat Genet 2013, Blood 2013, Nat Commun 2018). The replication series included 2,237 ALL cases of non-European ancestry from the COG and St. Jude GWAS cohorts. For each GWAS dataset, the genotypes of ~10 million SNPs in each study were imputed. After filtering out SNPs on the basis of minor allele frequency and imputation quality, we assessed associations between ALL status and SNP genotype in each study using logistic regression. Risk estimates were combined through an inverse variance weighted fixed-effects meta-analysis. The meta-analysis identified 16 risk loci above genome-wide significance (P &amp;lt; 5 x 10-8), of which ten confirmed previously published associations. Of the six new candidate risk loci, four were validated in the replication series (P &amp;lt; 0.05): for all B-ALL at 9q21.3 (nearest gene TLE1), for hyperdiploid ALL at 5q31.1 (C5orf56) and 6p21.31 (BAK1), and for ETV6-RUNX1 positive ALL at 17q21.32 (IGF2BP1). As well as providing further evidence for the 21q22.3 (ERG) association for all B-ALL, we also identified novel risk variants with the hyperdiploid subtype-specific association. To gain insight into the biological basis of association signals, we examined the epigenetic landscape of risk regions in B-cells. Of particular note, hyperdiploid ALL-specific risk variant at 6p21 is located within an intron 1kb downstream of the BAK1 transcription start site and possess histone marks characteristic of active promoter activity and open chromatin accessibility. The top SNP at this locus falls within a transcription factor binding cluster, and the C-risk allele is associated with reduced BAK1 expression (P&amp;lt;2×10-16). Mendelian randomization analysis confirmed a significant association with BAK1 expression and ALL consistent with a causal relationship. Similarly, the ETV6-RUNX1-specific risk variant at 17q12 is located in the second intron of IGF2BP1 and is predicted to influence topological associated domain structure in cis. Interestingly, ETV6-RUNX1 positive ALL leukemia cells showed a dramatic overexpression of IGF2BP1 compared to those without this fusion gene (P=3.7×10-23), suggesting its potential role in the pathogenesis of this ALL subtype. Analysis of disruption of transcription factor binding sites at ALL risk loci genome wide identified over-representation of PBX1 (P=0.007), TCF3 (P=0.007), ETS1 (P=0.009), RUNX1 (P=0.012) and ERG (P=0.030), BRD4 (P=0.007), and NR3C1 (P=0.009). Many of these transcription factors are also somatically mutated in ALL, pointing to multiple mechanisms by which they can contribute to leukemogenesis. Using the Linkage Disequilibrium Adjusted Kinships method, we estimated that ALL risk loci identified so far accounted for 31% of the total variance in genetic risk of this cancer. Polygenic risk score analysis indicates that an individual in the top 1% of genetic risk would have a 4.7-fold increased risk of ALL when compared to an individual with median genetic risk. In summary, our study provides further evidence for inherited susceptibility to ALL and support for subtype specificity at risk loci. Our findings also highlight a model of ALL pathogenesis relying on transcriptional deregulation, particularly of genes involved in B cell differentiation. Disclosures Raetz: Pfizer: Research Funding. Mullighan:Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel. Hunger:Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Jazz: Honoraria; Novartis: Consultancy. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10−208, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10−17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10−5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

A Sex-Stratified Genome-Wide Association Study of Tuberculosis Using a Multi-Ethnic Genotyping Array.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males than in females. While socio-economic status, behavior and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. A total of 810 individuals (410 cases and 405 controls) from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome (8,27,386 variants) and X chromosome (20,939 variants) in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.

The toll-like receptor (TLR) signaling pathway plays an important role in the innate immune responses and antigen-specific acquired immunity. Aberrant activation of the TLR pathway has a significant impact on carcinogenesis or tumor progression. Therefore, we hypothesize that genetic variants in the TLR signaling pathway genes are associated with overall survival (OS) of patients with non-small cell lung cancer (NSCLC). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate associations between genetic variants of 165 TLR signaling pathway genes and NSCLC OS using the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). The results were further validated by the Harvard Lung Cancer Susceptibility GWAS dataset. Specifically, we identified IRAK2 rs779901 C > T as a predictor of NSCLC OS, with a variant-allele (T) attributed hazards ratio (HR) of 0.78 [95% confidence interval (CI) = 0.67-0.91, P = 0.001] in the PLCO dataset, 0.84 (0.72-0.98, 0.031) in the Harvard dataset, and 0.81 (0.73-0.90, 1.08x10-4 ) in the meta-analysis of these two GWAS datasets. In addition, the T allele was significantly associated with an increased mRNA expression level of IRAK2. Our findings suggest that IRAK2 rs779901 C > T may be a promising prognostic biomarker for NSCLC OS.

Abstract 2077: Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Abstract Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. To date, few prognostic factors have been identified to be associated with survival in patients with osteosarcoma. We conducted an international, multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma. Subjects were genotyped as part of our previously published osteosarcoma susceptibility GWAS, including 523 patients of &amp;gt;80% European ancestry and 109 patients from Brazil. We performed a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. Cox models were adjusted for age at diagnosis, gender, significant principal components, and study/center. SNPs that reached P&amp;lt;10-4 in patients of European ancestry were followed up in patients from Brazil. The results were combined across case sets using a random-effects meta-analysis, and between-sets heterogeneity was evaluated using Cochran's Q chi-squared statistic and the I2 metric. Age (P&amp;lt;0.001) and presence of metastases at diagnosis (P&amp;lt;0.001) were associated with patient survival. In the combined analysis of 632 patients, the strongest association was SNP rs55933544, which was inversely associated with overall survival at genome-wide significance (HR=1.89 per copy of the T allele; 95% CI 1.5-2.4; P=1.3×10-8; I2=0%). Rs5593354 is located in intron 23 of the GLDC gene on chromosome 9p24.1, adjacent to the IL33 gene. This association was consistent across both the European (HR=1.9; P=1.6×10-6) and Brazilian (HR=2.1; P=8.4×10-3) case sets, and after adjustment for metastatic disease at diagnosis (combined HR=1.92; P=1.3×10-8), suggesting that this locus affects overall survival independent of metastatic disease. Kaplan-Meier curve analyses indicated a statistically significant difference between survival rates over time (log-rank test P&amp;lt;0.001) for both the dominant and multiplicative models for rs55933544. Using publicly available data, the risk allele was associated with lower expression of IL33, and lower expression of IL33 in osteosarcoma tumors was associated with worse survival in an independent set of 112 osteosarcomas (P&amp;lt;0.05). In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biologic underpinnings of this susceptibility locus. Citation Format: Roelof Koster, Orestis A. Panagiotou, William A. Wheeler, Eric Karlins, Julie M. Gastier-Foster, Silvia Regina Caminada de Toledo, Antonio S. Petrilli, Adrienne M. Flanagan, Roberto Tirabosco, Irene L. Andrulis, Jay S. Wunder, Nalan Gokgoz, Ana Patiño-Garcia, Fernando Lecanda, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, David M. Thomas, Mandy L. Ballinger, Richard Gorlick, Donald A. Barkauskas, Logan G. Spector, Margaret Tucker, Belynda Hicks, Meredith Yeager, Robert Hoover, Stephen J. Chanock, Sharon A. Savage, Lisa J. Mirabello. Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2077.

Erratum: "Genome-wide Association Study of Susceptibility to Particulate Matter-Associated QT Prolongation".

[This corrects the article DOI: 10.1289/EHP347.].

Genome-wide Association Study of Susceptibility to Particulate Matter-Associated QT Prolongation.

Background:Ambient particulate matter (PM) air pollution exposure has been associated with increases in QT interval duration (QT). However, innate susceptibility to PM-associated QT prolongation has not been characterized.Objective:To characterize genetic susceptibility to PM-associated QT prolongation in a multi-racial/ethnic, genome-wide association study (GWAS).Methods:Using repeated electrocardiograms (1986–2004), longitudinal data on in diameter (), and generalized estimating equations methods adapted for low-prevalence exposure, we estimated approximately interactions among nine Women’s Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (), then combined subpopulation-specific results in a fixed-effects, inverse variance-weighted meta-analysis.Results:A common variant (rs1619661; coded allele: T) significantly modified the association (). At concentrations percentile, QT increased 7 ms across the CC and TT genotypes: 397 (95% confidence interval: 396, 399) to 404 (403, 404) ms. However, QT changed minimally across rs1619661 genotypes at lower concentrations. The rs1619661 variant is on chromosome 10, 132 kilobase (kb) downstream from CXCL12, which encodes a chemokine, stromal cell-derived factor 1, that is expressed in cardiomyocytes and decreases calcium influx across the L-type channel.Conclusions:The findings suggest that biologically plausible genetic factors may alter susceptibility to -associated QT prolongation in populations protected by the U.S. Environmental Protection Agency’s National Ambient Air Quality Standards. Independent replication and functional characterization are necessary to validate our findings. https://doi.org/10.1289/EHP347

Common genetic variants in the immunoglobulin heavy chain locus and their differential impact on group A streptococcal disease susceptibility: a comparative meta-analysis of genetic susceptibility studies

BackgroundGlobally the diverse diseases associated with Streptococcus pyogenes infection are an important public health concern. Building on our recent discovery of a putative rheumatic heart disease susceptibility signal in the immunoglobulin heavy chain locus (IGH), we sought to identify variants in this poorly understood locus with shared and opposing effects on susceptibility to S pyogenes diseases focusing on rheumatic heart disease and invasive S pyogenes, which have mutually exclusive clinical phenotypes. MethodsWe conducted a comparative meta-analysis of our genome-wide association studies of susceptibility to rheumatic heart disease and invasive S pyogenes. Patients with rheumatic heart disease were recruited in Fiji, New Caledonia, and Samoa, and patients with invasive S pyogenes in the UK, Kenya, and New Caledonia. Controls were drawn from the same populations with additional controls for the rheumatic heart disease study from other Pacific Island nations. We searched for shared and opposing IGH loci using z-scores from the underlying analyses and used multinominal logistic regression to estimate effect sizes. FindingsAfter quality control, there were 1028 cases and 2057 controls in the rheumatic heart disease study and 147 cases and 3003 controls in the invasive S pyogenes study with an overlap of 1669 common variants in the IGH locus. We identified a shared effect signal 3·4 kb upstream from the IGHV1-69 gene segment overlapping a putative transcription factor binding site and an opposing effect signal peaking at a missense variant in the second exon of the IGHV1-69 gene segment corresponding to the IGHV3-66*03 allele. After conditioning on the IGHV4-61*02 allele, which we have previously found associated with rheumatic heart disease, the lead shared effect single nucleotide polymorphism (SNP) (rs28627956) conferred increased risk of invasive S pyogenes but with negligible effect on risk of rheumatic heart disease (odds ratio 1·45 [95% CI 1·16–1·73] and 1·06 [0·87–1·24], respectively), whereas the lead opposing effect SNP (rs6423677) conferred reduced risk of invasive S pyogenes (0·75, 0·61–0·96) and increased risk of rheumatic heart disease (1·15, 0·98–1·38). InterpretationGermline IGH polymorphism is predicted to modify infectious and autoimmune disease susceptibility, although robust examples of such effects are scarce. Our results suggest that such polymorphism might have differential effects on susceptibility to S pyogenes disease, plausibly through coding and regulatory mechanisms. Our results provide new insight into the pathogenesis of these two neglected diseases as well as into the complex interplay between infectious and inflammatory disease. FundingBritish Heart Foundation, British Medical Association, European Society of Clinical Microbiology and Infectious Diseases, UK Medical Research Council, Wellcome Trust.