Meta-analysis Of Association Studies Research Articles

PASTRY: achieving balanced power for detecting risk and protective minor alleles in meta-analysis of association studies with overlapping subjects

BackgroundMeta-analysis is a statistical method that combines the results of multiple studies to increase statistical power. When multiple studies participating in a meta-analysis utilize the same public dataset as controls, the summary statistics from these studies become correlated. To solve this challenge, Lin and Sullivan proposed a method to provide an optimal test statistic adjusted for the correlation. This method quickly became the standard practice. However, we identified an unexpected power asymmetry phenomenon in this standard framework. This can lead to unbalanced power for detecting protective minor alleles and risk minor alleles.ResultsWe found that the power asymmetry of the current framework is mainly due to the errors in approximating the correlation term. We then developed a meta-analysis method based on an accurate correlation estimator, called PASTRY (A method to avoid Power ASymmeTRY). PASTRY outperformed the standard method on both simulated and real datasets in terms of the power symmetry.ConclusionsOur findings suggest that PASTRY can help to alleviate the power asymmetry problem. PASTRY is available at https://github.com/hanlab-SNU/PASTRY.

Genetic liability between COVID-19 and heart failure: evidence from a bidirectional Mendelian randomization study

BackgroundPrevious studies have observed inconsistent associations between coronavirus disease 2019 (COVID-19) and heart failure (HF), but these studies were prone to bias based on reverse causality and residual confounding factors. We aimed to investigate genetic liability between COVID-19 and heart failure using a bidirectional Mendelian randomization study.MethodsThe causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and HF are determined by using a bidirectional Mendelian randomization analysis. We drew on summary statistics from the largest HF genome-wide association study (GWAS) meta-analysis on individuals of European ancestry, which included 47,309 HF patients and 930,014 controls. The inverse variance weighted (IVW), an adaption of the Egger regression (MR-Egger), the weighted median, and weighted model were conducted for the Mendelian randomization analysis to estimate a causal effect. To confirm the stability, we performed a “leave-one-out” approach for the sensitivity analysis.ResultsGenetically predicted severe COVID-19 was not significantly associated with the risk of HF [odds ratio (OR), 1.003; 95% confidence interval (CI), 0.969–1.037; p = 0.867]. The IVW demonstrated that there was no association between genetically hospitalized COVID-19 infection and HF risk [OR, 1.009; 95% CI, 0.939–1.085; p = 0.797]. There was no evidence to support the association between genetically determined COVID-19 and the risk of HF [OR, 1.066; 95% CI, 0.955–1.190; p = 0.253]. In addition, genetically predicted HF was also not causally associated with COVID-19 [OR, 1.162; 95% CI, 0.824–1.639; p = 0.393]. MR-Egger analysis indicated no evidence of directional pleiotropy.ConclusionThe current bidirectional Mendelian randomization analysis overcomes the limitations of observational studies. Our findings indicated that there is no causal association between COVID-19 and HF.

The Association Between Vitamin C and Cancer: A Two-Sample Mendelian Randomization Study.

In recent years, many studies have indicated that vitamin C might be negatively associated with the risk of cancer, but the actual relationship between vitamin C and cancer remains ambivalent. Therefore, we utilized a two-sample Mendelian randomization (MR) study to explore the causal associations of genetically predicted vitamin C with the risk of a variety of cancers. Single-nucleotide polymorphisms (SNPs) associated with vitamin C at a significance level of p < 5 × 10–8 and with a low level of linkage disequilibrium (LD) (r2 < 0.01) were selected from a genome-wide association study (GWAS) meta-analysis of plasmid concentration of vitamin C consisting of 52,018 individuals. The data of the GWAS outcomes were obtained from United Kingdom Biobank, FinnGen Biobank and the datasets of corresponding consortia. In the inverse-variance weight (IVW) method, our results did not support the causal association of genetically predicted vitamin C with the risk of overall cancer and 14 specific types of cancer. Similar results were observed in sensitivity analyses where the weighted median and MR-Egger methods were adopted, and heterogeneity and pleiotropy were not observed in statistical models. Therefore, our study suggested that vitamin C was not causally associated with the risk of cancer. Further studies are warranted to discover the potential protective and therapeutic effects of vitamin C on cancer, and its underlying mechanisms.

Systematic review and meta-analysis of candidate gene association studies of benign prostate hyperplasia

BackgroundBenign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH.MethodsA comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd’s ratio (OR) and 95% confidence intervals (CIs). Begg’s funnel plot was used to assess the potential for publication bias.ResultsWe found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03–2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38–27.68) and Asian (OR = 1.42, 95% CI = 0.99–2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models.ConclusionSignificant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.

Unveiling genetic variants for age-related sarcopenia by conducting a genome-wide association study on Korean cohorts

Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the ‘mRNA destabilisation’ biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia.

Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer

BackgroundPreclinical and epidemiological studies indicate a potential chemopreventive role of low-density lipoprotein cholesterol (LDL-C) -lowering drugs in the risks of breast cancer and prostate cancer, but the causality remains unclear. We aimed to evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) with risks of breast cancer and prostate cancer using a two-sample Mendelian randomization (MR) method.MethodsSingle-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study (GWAS) meta-analysis from the Global Lipids Genetics Consortium (GLGC; up to 188,577 European individuals) were used to proxy inhibition of HMG-CoA reductase, NPC1L1, and PCSK9. Summary statistics with outcomes were obtained from a GWAS meta-analysis of the Breast Cancer Association Consortium (BCAC; 228,951 European females) and a Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL; 140,254 European males) consortium. SNPs were combined into multiallelic models and MR estimates representing lifelong inhibition of targets were generated using the inverse-variance weighted method.ResultsGenetically proxied inhibition of HMG-CoA reductase (OR: 0.84; 95% CI 0.74–0.95; P = 0.005) and NPC1L1 (OR: 0.72; 95% CI 0.58–0.90; P = 0.005) equivalent to a 1-mmol/L (38.7 mg/dL) reduction in LDL-C was associated with reduced breast cancer risk. There were no significant associations of genetically proxied inhibition of PCSK9 with breast cancer. In contrast, genetically proxied inhibition of PCSK9 (OR: 0.81; 95% CI 0.73–0.90; P < 0.001) but not HMG-CoA reductase and NPC1L1 was negatively associated with prostate cancer. In the secondary analysis, genetically proxied inhibition of HMG-CoA reductase (OR: 0.82; 95% CI 0.71–0.95; P = 0.008) and NPC1L1 (OR: 0.66; 95% CI 0.50–0.86; P = 0.002) was associated with estrogen receptor-positive breast cancer, whereas there was no association of HMG-CoA reductase and NPC1L1 with estrogen receptor-negative breast cancer.ConclusionsGenetically proxied inhibition of HMG-CoA reductase and NPC1L1 was significantly associated with lower odds of breast cancer, while genetically proxied inhibition of PCSK9 was associated with reduced risk of prostate cancer. Further randomized controlled trials are needed to confirm the respective roles of these LDL-C-lowering drugs in breast cancer and prostate cancer.

Causal effects of atrial fibrillation on brain white and gray matter volume: a Mendelian randomization study

BackgroundAtrial fibrillation (AF) and brain volume loss are prevalent in older individuals. We aimed to assess the causal effect of atrial fibrillation on brain volume phenotypes by Mendelian randomization (MR) analysis.MethodsThe genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis (15,993 AF patients and 113,719 controls of European ancestry). The outcome summary statistics for head-size-normalized white or gray matter volume measured by magnetic resonance imaging were provided by a previous GWAS of 33,224 white British participants in the UK Biobank. Two-sample MR by the inverse variance–weighted method was performed, supported by pleiotropy-robust MR sensitivity analysis. The causal estimates for the effect of AF on ischemic stroke were also investigated in a dataset that included the findings from the MEGASTROKE study (34,217 stroke patients and 406,111 controls of European ancestry). The direct effects of AF on brain volume phenotypes adjusted for the mediating effect of ischemic stroke were studied by multivariable MR.ResultsA higher genetic predisposition for AF was significantly associated with lower grey matter volume [beta −0.040, standard error (SE) 0.017, P=0.017], supported by pleiotropy-robust MR sensitivity analysis. Significant causal estimates were identified for the effect of AF on ischemic stroke (beta 0.188, SE 0.026, P=1.03E−12). The total effect of AF on lower brain grey matter volume was attenuated by adjusting for the effect of ischemic stroke (direct effects, beta −0.022, SE 0.033, P=0.528), suggesting that ischemic stroke is a mediator of the identified causal pathway. The causal estimates were nonsignificant for effects on brain white matter volume as an outcome.ConclusionsThis study identified that genetic predisposition for AF is significantly associated with lower gray matter volume but not white matter volume. The results indicated that the identified total effect of AF on gray matter volume may be mediated by ischemic stroke.

Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability.

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p < 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = −0.0264, p value = 3.5 × 10–8) in the discovery panel and was replicated in replication panel (beta = −0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

Introduction and hypothesisFamily and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations.MethodsUpdating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria.ResultsWe screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46–0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11–1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39–0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66–0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies.ConclusionThe genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.

Systematic Review and Meta-Analysis of Candidate Gene Association Studies With Fracture Risk in Physically Active Participants

Background: Fractures are common in physically active populations and genetic differences may mediate injury risk.Objective: To meta-analyse the pooled results of candidate gene association studies with non-osteoporotic fracture risk in physically active humans.Methods: Systematic searching of databases returned 11 eligible studies published in English. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were produced using allele contrast, recessive and homozygote contrast meta-analysis models to evaluate associations of risk alleles in the COL1A1 (rs1800012), COL2A1 (rs412777), CTR (rs1801197), ESR1 (rs2234693 and rs9340799) LRP5 (rs3736228), VDR (rs10735810, rs7975232, rs1544410, and rs731236) genes with fracture incidence.Results: Eligible study quality was generally low (7/11) and no significant overall effect was found for any genetic variant with any comparison model (p > 0.05). A trivial reduction in fracture risk was found for female participants with the COL1A1 Sp1 (rs1800012) T allele (OR = 0.48, 95% CI = 0.25–0.91, p = 0.03, d = –0.18).Conclusions: No overall effect was found from the pooled results of included genetic variants on fracture risk in physically active participants. The COL1A1 Sp1 rs1800012 T allele may reduce fracture risk in physically active females but further high-quality research with sex-specific analysis is required.Trial Registration: (PROSPERO; CRD42018115008).

P0228THE NEFIGARD TRIAL: THE EFFECT OF NEFECON® (BUDESONIDE) IN PATIENTS WITH PRIMARY IGA NEPHROPATHY AT RISK OF DEVELOPING END-STAGE RENAL DISEASE

Abstract Background and Aims Since the first description of IgA nephropathy (IgAN) over 50 years ago, it has been recognised that the mucosal immune system plays a crucial role in the pathogenesis of this common global cause of kidney failure. Recently, particular attention has focussed on the importance of the gut-associated lymphoid tissue (GALT) as the potential source of the poorly O-galactosylated IgA1 that triggers the formation of nephritogenic immune complexes in IgAN. Pathway analysis based on a large meta-analysis of genome wide association studies identified the intestinal immune network for IgA production as the most enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway in IgAN. Furthermore, separate studies have shown that the IgA in glomerular IgA deposits is indistinguishable from mucosal IgA. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. After 9 months’ treatment, urine protein–creatinine ratio (UPCR) was reduced by 29.3% in the NEFECON® 16 mg group compared with the placebo group. Estimated glomerular filtration rate (eGFR) dropped 4.7 ml/min/1.73 m2 in the placebo group with no deterioration seen in the NEFECON® 16 mg group. Incidence of patients reporting adverse events was similar in all groups. These data led to the design of the NefIgArd study which aims to assess the efficacy, safety, and tolerability of NEFECON® 16 mg in patients with IgAN at risk of end-stage renal disease. Method The NefIgArd study is a randomised, double-blind, placebo-controlled Phase 3 trial, with two parts – PART A a 15–35-day screening period, 9-month treatment and 3-month follow-up period; and PART B a 12-month no-treatment follow-up period (Figure). The study is recruiting across 146 nephrology clinics in 19 countries. Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria &amp;gt;1 g/24 h and eGFR between 35 and 90 ml/min per 1.73 m2 (CKD-EPI) despite optimised renin–angiotensin system blockade. Patients are randomised on a 1:1 ratio to NEFECON® 16 mg/day or placebo. Consistent with the Kidney Health Initiative White Paper “Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy” published in early 2019, the primary outcome of Part A is to assess the effect of NEFECON® 16 mg on 24 h UPCR at 9 months compared with placebo. The Part B primary outcome is based on data presented at the NKF/FDA/EMA workshop in March 2018 that supported eGFR slope as an endpoint for full approval and will assess the effect of NEFECON® 16 mg on a 2-year eGFR-based endpoint compared with placebo. In comparison with other studies that are recruiting, we believe that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of non-protocol treatments and loss of patients from the study that could dilute the true treatment effect of NEFECON®. Results As of 1 January 2020, 207 patients have been randomised, and Part A is expected to complete in Q4 2020, with Part B completing in 2022. To ensure the NefIgArd study results are fully translatable to the global IgAN population, NefIgArd will also open in China in 2020. Conclusion The NefIgArd study builds on the experience of the NEFIGAN trial, the largest commercially sponsored study ever completed in IgAN. The design of the NefIgArd study has used state-of-the-art data to evaluate kidney outcomes, using proteinuria as a reasonably likely surrogate of the effect of NEFECON® on long-term kidney outcomes and confirming long-term renoprotection using an NKF/FDA/EMA-suggested eGFR-based endpoint as a basis for full approval.

Abstract WP216: Epigenome-Wide Association Study of Cerebral White Matter Hyperintensities

Background: Cerebral white matter hyperintensities (WMH) on MRI are typical markers of small vessel disease and strong radiological correlates of stroke and age-related cognitive decline. Despite a recognized high heritability, the molecular basis of WMH has not been fully characterized. In particular, the contribution of epigenetic modifications, such as DNA methylation, has not been explored. Methods: We conducted a meta-analysis of epigenome-wide association studies of WMH burden in up to 5777 elderly participants of European and African ancestry from 9 population-based cohorts using blood-derived DNA methylation measured on the Infinium HumanMethylation450 BeadChip. Cohort-specific associations between burden of WMH and DNA methylation beta values were estimated using linear mixed-effect models and combined in a sample-size weighted fixed-effect meta-analysis. In addition, we used two different approaches to identify differentially methylated regions (DMRs), which may be more informative than individual loci. Bonferroni correction and False Discovery Rates were used to account for the multiple tests. Results: Single-site analyses identified a CpG site within the CLDN5 gene significantly associated with WMH (P= 2.3x10 -7 ). Claudin-5 is an endothelial-specific component in the brain vasculature and regulates blood brain barrier permeability. Region-based analyses, which leverage the correlations between nearby CpG sites identified several DMRs significantly associated with WMH burden including: PRMT1, BTBD17, and IFITM10 (P=1.4x10 -10 , 2.3x10 -8 , and 3.6x10 -7 , respectively). PRMT1 encodes the Protein Arginine N-methylase 1, which methylates histones in genes involved in glioblastomagenesis. Mice lacking this gene are characterized by severe defects in oligodendrocyte maturation processes. The function of BTBD17 and IFITM10 is not characterized but both are expressed in the brain and exhibit changes in expression in response to viral infection. Conclusions: Consistent with our previously reported genetic association studies, this genome-wide DNA methylation analysis supports a role of genes involved in glial cell function in WMH etiology. It also suggests a novel role of genes involved in viral response.

Abstract 2970: Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma

Abstract Ewing sarcoma (EWS) is a rare pediatric tumor predominantly occurring in children of European ancestry and is characterized by the pathognomonic EWSR1-FLI1 fusion oncogene. To identify germline susceptibility loci associated with EWS risk, we performed a genome-wide association study (GWAS) meta-analysis of 749 EWS cases and 1,378 unaffected individuals of European ancestry from sample collections within the Institut Curie, National Cancer Institute and the Childhood Cancer Survivor Study. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1 as well as identified novel loci at 6p25.1, 8q24.23, 20p11.22 and 20p11.23 (P-values&amp;lt;5×10-8). These seven EWS susceptibility loci discovered in only 749 cases make EWS one of the most productive GWAS studied cancers when considering a locus to case discovery ratio. All estimated effect estimates were high for cancer GWAS with odds ratios in excess of 1.7 observed. These high per allele effects among relatively common germline variants are striking in light of the rarity of EWS cases and lack of evidence of EWS as part of a familial cancer syndrome and therefore suggest a distinctive genetic architecture for EWS. Interestingly, in silico bioinformatics analysis identified that most EWS susceptibility loci reside near GGAA nucleotide repeat sequences where binding of the EWSR1-FLI1 fusion protein occurs. ChIP-seq analyses confirmed in vivo binding of EWSR1-FLI1, suggesting germline variation in these regions could alter EWSR1-FLI1 binding and potentially deregulate neighboring genes. To identify genes with allele specific expression differences, we carried out expression quantitative trait locus (eQTL) analyses at each identified EWS susceptibility locus. We identified eQTLs for plausible candidate genes at 6p25.1 with RREB1, a RAS-responsive element, and at 20p11.23 with KIZ, a centrosomal stabilization protein. We also noted the 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS, although no eQTL was observed in our expression data. Furthermore, knockdown of EWSR1-FLI1 in EWS cell lines indicated a more than 2-fold difference in expression of RREB1 and NKX2-2, further supporting the role of specific regulation of these genes by EWSR1-FLI1 and suggesting RREB1 and NKX2-2 may be transcription factors involved in core regulatory circuitries of EWS. Overall, our study suggests a distinctive underlying genetic architecture for EWS in which moderate risk common germline variants interact with EWSR1-FLI1 binding to alter expression of nearby target genes. Citation Format: Mitchell J. Machiela, Thomas G. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdette, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, Olivier Delattre. Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma [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 2970.

Collagen type-I A2 gene polymorphisms and susceptibility to intracranial aneurysms: a meta-analysis of genetic association studies

ABSTRACTBackground: The development, evolution and rupture of intracranial aneurysms are in part related to genetic factors. The role of collagen type-I a2 genetic polymorphisms has not been clarified yet.Material and methods: A meta-analysis was realized by means of a genotype model-fitting process (allele contrast, recessive, dominant, additive and co-dominant), and a model-free approach using the generalized odds ratio. The latter was assessed in association to the degree of dominance (h-index).Results: No statistically significant association was documented between EX28 G>C collagen type-I a2 variant and intracranial aneurysms (generalized odds ratio = 1.23, 95% confidence interval = 0.57, 2.63). Significant associations between INT46 T>G collagen type I a2 variant and intracranial aneurysms were documented in three models, the dominant [0.52 (0.38, 069)], the co-dominant [0.50 (0.32, 0.78)] and the allele contrast models [0.63 (0.49, 0.82)]. The generalized odds ratio was estimated to be as high as 1.94 (1.23, 3.06). The degree of dominance (h-index = −1.54) indicated that the TG genotype was characterized by lower risk of developing intracranial aneurysms compared to the TT genotype.Conclusions: The available literature data demonstrated that there is no association of collagen type-(2a) and intracranial aneurysms, through EX28 G>C (rs42524) polymorphism according to the model-fitting process and the model-free approach. Regarding the INT46 T>G (rs2621215) polymorphisms, the latter models indicated that there could be a protective effect of the G-allele against the development of intracranial aneurysms. However, the majority of studies are from East Asia, therefore the results are applicable primarily to that patient population.

Abstract 1303: A genome-wide association study of prostate cancer in Latinos

Abstract Recent studies estimate that individuals of African or Latin American ancestry represent less than 4% of samples analyzed to date in genome-wide association studies. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts in these populations. Here, we performed a genome-wide association study (GWAS) meta-analysis of prostate cancer in Latino men to search for risk loci that may be important in this population. We combined GWAS data for 1034 cases and 1046 controls genotyped with the Illumina 660 Beadarray with GWAS data for 1235 cases and 1053 controls genotyped with the Illumina Oncoarray as part of the ELLIPSE U19 GAME-ON Consortium. A total of ~11 million genotyped and imputed SNPs of ≥1% frequency were tested for association with prostate cancer risk in logistic regression models controlling for age, study and genetic ancestry. Genome-wide significant associations were observed with 24 variants all located at 8q24 (128.484-128.548), and which capture the first reported prostate cancer susceptibility locus in ‘region 1’ of 8q24. The most significant association genome-wide was with SNP rs7824776 (risk allele frequency, 0.35; OR=1.69, p=3.4x10-11). No novel genome-wide significant associations were noted outside of 8q24. We observed a high degree of generalizability of known prostate cancer risk loci, with 78 (76%) of the 103 known risk variants having effects that were directionally consistent in their association with prostate cancer risk as previously reported, of which 31 (30%) were statistically significant with p &amp;lt; 0.05. In addition to these findings from the largest GWAS of prostate cancer in Latinos conducted to date, we will also present the results investigating effect heterogeneity by local ancestry (i.e. proportion Native American vs. European). In addition, we will present a comparison of polygenic risk models between Latinos, African Africans and men of European ancestry that incorporate the known risk loci to better understand how genetic risk tracks with population differences in prostate cancer incidence. Citation Format: Hannah Hopp, Sue Ingles, Chad Huff, Xin Sheng, Brandi Weaver, Mariana Stern, Sara Strom, Ian Thompson, David Conti, Christopher A. Haiman. A genome-wide association study of prostate cancer in Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1303. doi:10.1158/1538-7445.AM2017-1303

A genome-wide association study (GWAS) meta-analysis of chemotherapy-associated cognitive impairment (CACI) in Asian early-stage breast cancer patients (ESBC).

10096 Background: Genetic variations among genes regulating neuronal function, neurotransmission and plasticity may contribute to varying risk of CACI. In order to fully elucidate the complex genetic structure underlying CACI, a GWAS meta-analysis was performed to identify genetic variants associated with CACI among ESBC patients. Methods: A GWAS meta-analysis of two independent cohorts totaling 266 chemotherapy-receiving ESBC patients (mean age: 51.0 ± 9.2 years; 80.8% Chinese) was performed. Patients’ self-perceived cognitive function was assessed using the validated FACT-Cog (v.3). Genome-wide genotyping was performed using the Illumina HumanOmniExpress-24 version 1.1 BeadChips kits. Each beadchip contains over 700,000 genetic markers. Covariates included in the meta-analysis were the first two dimensions of the multi-dimensional scaling. Results: After applying stringent quality control measures and removing four population outliers, data from 546,399 SNPs were available for 84 cases and 170 controls. In the meta-analysis, two SNPs (rs6443264 and rs4686371) exceeded the suggestive threshold of P &lt; 1×10-5 (Table). Following adjustment for the first two MDS dimensions in the meta-analysis, both SNPs remained as top two SNPs with P &lt; 1×10-4. Both rs6443264 and rs4686371 are located in chromosome 3p25 and lie in the intronic regions encoding OGG1 and ARPC4 genes, respectively. Alteration of the OGG1 gene could compromise the functions of downstream neuronal genes, and modification of the ARPC4 gene could affect the formation of the actin-related protein 2/3 complex and impair memory formation. Conclusions: To the best of our knowledge, this is the first GWAS meta-analysis to identify two loci, namely rs6443264 and rs4686371 that are suggestive of genome-wide association with CACI among Asian ESBC patients. [Table: see text]

Abstract 447: Deep Transcriptomic Analysis of Human Vascular Cells Identifies Risk Genes for Common Vascular Diseases

The most recent Genome-wide Association Study (GWAS) meta-analysis has reported a total of 58 genomic loci to be statistically significantly associated with genetic susceptibility to Coronary Artery Disease (CAD) (Consortium, 2015). Many of these loci also associate with other phenotypes, with the majority being lipid traits (Tada et al., 2014). But also hypertension, stroke (Dichgans et al., 2014) and migraine (Pickrell et al., 2016) appear to share genetic determinants with CAD. To functionally annotate the genomic loci harboring these association SNPs we sequenced the transcriptomes of 20 same donor human coronary artery endothelial (EC) and smooth muscle cell (SMC) lines. Deep RNA-Sequencing was used to assess Differential Gene Expression, Differential Splicing and Allele-Specific Expression. Focusing on GWAS loci for vascular phenotypes (CAD, stroke, migraine) we identified genes which display allele-specific differences in mRNA expression or splicing. We propose these genes as suitable targets for follow up studies. Consortium, C.A.D. (2015). A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nature genetics 47, 1121-1130. Tada, H., Won, H.H., Melander, O., Yang, J., Peloso, G.M., and Kathiresan, S. (2014). Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease. Circulation Cardiovascular genetics 7, 583-587. Dichgans, M., Malik, R., Konig, I.R., Rosand, J., Clarke, R., Gretarsdottir, S., Thorleifsson, G., Mitchell, B.D., Assimes, T.L., Levi, C., et al. (2014). Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke; a journal of cerebral circulation 45, 24-36. Pickrell, J.K., Berisa, T., Liu, J.Z., Segurel, L., Tung, J.Y., and Hinds, D.A. (2016). Detection and interpretation of shared genetic influences on 42 human traits. Nature genetics 48, 709-717.

An economic model for the use of yoghurt in type 2 diabetes risk reduction in the UK

In the UK, diabetes accounts for approximately 10% of the total UK National Health Service (NHS) resource expenditure, a figure that has been predicted to increase to 17% by 2035/2036. Meta-analysis of association studies indicate that yogurt consumption is potentially protective against type 2 diabetes (T2D). The purpose of this study was to explore the potential economic benefit to the UK NHS of a population increase in yoghurt consumption as a preventative measure against development of T2D. A patient simulation model was constructed for adults in the UK over the age of 25 years old using incidence rates for developing T2D with both current and increased yoghurt consumption. The reduction in risk in developing T2D associated with higher yoghurt consumption was taken from a meta-analysis of studies of dairy consumption on T2D risk. In each annual cycle of the model a patient could develop complications and comorbidities that are known to be more common in patients with T2D. Incidence rates for these conditions for diabetics and non-diabetics were taken from published studies. The model had a 25 year time horizon. The model predicts that increasing average yoghurt consumption by adults over 25 years of age in the UK by 100g daily could result in 388,000 fewer people developing T2D over 25 years. This could save the UK NHS £2.3bn in direct T2D treatment costs and the costs of treating T2D associated complications. In addition, 267,000 QALYs would be generated. If the NHS values a QALY valued at £20,000, this would mean that the NHS should be prepared to pay £5.5bn for an intervention that generated the same number of QALYs. Increasing yoghurt consumption in the adult population of the UK by 100g per day could generate substantial cost savings to the NHS as well as significant patient benefit through reductions in the incidence of T2D.

PTU-061 Human Intestinal Transcriptome Analysis in Inflammatory Bowel Disease

Introduction Inflammatory Bowel Disease (IBD) is a complex genetic disease characterised by chronic inflammation of the gastro-intestinal tract. Genome-wide association study (GWAS) meta-analysis and replication has identified over 200 genomic regions involved in IBD susceptibility although only a few of the associated single nucleotide polymorphisms (SNPs) directly alter the coding sequence of a gene. In addition, >92 of the IBD-susceptibility loci are known to co-localise with active regulatory elements, suggesting the majority of IBD associated SNPs alter gene expression in some way. Here we employ whole transcriptome sequencing to investigate the role of altered gene expression in intestinal tissue. Methods Patients and non-IBD control individuals were recruited after informed consent through endoscopy clinics at Guy’s and St Thomas’ Hospital, London. Whole RNA was extracted from 2–4 colonic biopsies from 104 IBD patients (76 CD, 28 UC) and 24 non-IBD controls and ribo-depleted (Ribo-zero, Illumina). We performed whole RNA sequencing using Illumina TruSeq and HiSeq2500 on pools of 4 indexed RNA libraries across 1–2 lanes. Quality control of sequence reads was performed via FastQC. Subsequent alignment and assembly, quantification and differential expression (DE) analysis of each transcript was performed using Tophat2, Cufflinks, Cuffmerge and EdgeR. Results So far a detailed bioinformatics analysis has been carried out on the first 32 whole RNA-seq libraries. We have observed expression above background (FPKM > 1) for approximately 46% of all known transcripts located within known IBD susceptibility loci. DE analysis identified 249 transcripts with significant difference in expression (q Conclusion We have generated high coverage whole RNAseq data on intestinal biopsy samples from 128 individuals. We have shown Disclosure of Interest None Declared