Controls Of European Ancestry Research Articles

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.

Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.

Identification of blood protein biomarkers associated with prostate cancer risk using genetic prediction models: analysis of over 140,000 subjects.

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant associations with PCa risk, including 16 previously reported proteins and eight novel proteins. Of them, 14 proteins showed negative associations and 10 showed positive associations with PCa risk. For 18 of the identified proteins, potential functional somatic changes of encoding genes were detected in PCa patients in The Cancer Genome Atlas (TCGA). Genes encoding these proteins were significantly involved in cancer-related pathways. We further identified drugs targeting the identified proteins, which may serve as candidates for drug repurposing for treating PCa. In conclusion, this study identifies novel protein biomarker candidates for PCa risk, which may provide new perspectives on the etiology of PCa and improve its therapeutic strategies.

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

IntroductionSeveral studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. MethodsUsing genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. ResultsGenetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07–2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44–4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96–1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03–1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. ConclusionA genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Association Between Prekallikrein and Stroke: A Mendelian Randomization Study.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P=5.44×10-5), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P=1.42×10-5), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P=3.75×10-4), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P=3.02×10-5). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

BackgroundGenome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92–0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88–0.94).ConclusionsOverall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

A Splicing Transcriptome-Wide Association Study Identifies Candidate Altered Splicing for Prostate Cancer Risk.

Prostate cancer (PCa) represents a huge public health burden among men. Many susceptibility genetic factors for PCa still remain unknown. In this study, we performed a large splicing transcriptome-wide association study (spTWAS) using three modeling strategies to develop alternative splicing genetic prediction models for identifying novel susceptibility loci and splicing introns for PCa risk by assessing 79,194 cases and 61,112 controls of European ancestry in the PRACTICAL, CRUK, CAPS, BPC3, and PEGASUS consortia. We identified 120 splicing introns of 97 genes showing an association with PCa risk at false discovery rate (FDR)-corrected threshold (FDR <0.05). Of them, 33 genes were enriched in PCa-related diseases and function categories. Fine-mapping analysis suggested that 21 splicing introns of 19 genes were likely causally associated with PCa risk. Thirty-five splicing introns of 34 novel genes were identified to be related to PCa susceptibility for the first time, and 11 of the genes were enriched in a cancer-related network. Our study identified novel loci and splicing introns associated with PCa risk, which can improve our understanding of the etiology of this common malignancy.

Mendelian Randomization Study of the Relationship Between Serum Matrix Metalloproteinases and the Occurrence of Sepsis

BackgroundObservational studies have shown that matrix metalloproteinases (MMPs) are associated with sepsis. However, it is unknown whether this association represents a causal relationship.MethodsMendelian randomization (MR) analysis was conducted to assess the potential causal role of circulating MMPs in sepsis. Single nucleotide polymorphisms (SNPs) associated with circulating MMPs levels were used as instrumental variables (IVs). In a sepsis genome-wide association study comprising 1573 cases and 454,775 European ancestry controls, we examined these IVs' effects using a two-sample MR study. Causal estimates were calculated using inverse variance weighting (IVW), the weighted median method, and MR-Egger analysis.ResultsGenetically predict that MMP-1 (OR = 1.011, 95% CI 0.772–1.325, p = 0.936), MMP-3 (OR = 1.036, 95% CI 0.862–1.244, p = 0.707), MMP-7 (OR = 1.206, 95% CI 0.960–1.515, p = 0.108), MMP-8 (OR = 1.041, 95% CI 0.949–1.144, p = 0.395), MMP-9 (OR = 1.101, 95% CI 0.831–1.458, p = 0.503), MMP-10 (OR = 1.028, 95% CI 0.840–1.260, p = 0.789) was not associated with the risk of sepsis.ConclusionsThe MR study does not provide evidence that circulating levels of MMPs (1, 3, 7, 8, 9, 10) were the causes of sepsis.

Causal effects of serum lipid biomarkers on early age-related macular degeneration using Mendelian randomization

BackgroundAge-related macular degeneration (AMD) is one of the major causes of vision loss. Early AMD needs to be taken seriously, but the causal effects of lipid biomarkers on early AMD remain unclear.MethodsIn this study, two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between seven serum lipid biomarkers (apolipoprotein A (ApoA), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], and triglycerides (TG)) and risk of early AMD. In total, 14,034 cases and 91,214 controls of European ancestry were included in the analysis (number of SNPs = 11,304,110).ResultsMR estimates revealed that a higher HDL-C level is strongly associated with increased risk of early AMD (OR = 1.25, 95% CI: 1.15–1.35, P = 2.61 × 10−8). In addition, level of ApoA is also positively associated with risk of early AMD (OR = 2.04, 95% CI: 1.50–2.77, P = 6.27 × 10−6). Conversely, higher levels of TG significantly decrease the risk of early AMD (OR = 0.77, 95% CI: 0.71–0.84, P = 5.02 × 10−10). Sensitivity analyses further supported these associations. Moreover, multivariable MR analyses, adjusted for the effects of correlated lipid biomarkers, yielded similar results.ConclusionThis study identifies causal relationships between elevated circulating HDL-C/ApoA levels and increased risk of early AMD, in addition to finding that TG specifically reduces the risk of early AMD. These findings contribute to a better understanding of the role of lipid metabolism in drusen formation, particularly in early AMD development.

Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).

A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × 10−7). Fine-mapping analyses supported 155 likely causal associations corresponding to 83 splicing introns of 55 genes. Eighteen causal splicing introns of 15 novel genes (EIF2D, WDR33, SAP130, BYSL, EPHB6, MRPL43, VEGFB, PPP1R13B, TLN2, CLUHP3, LRRC37A4P, CRHR1, LINC02210, ZNF45-AS1, and XPNPEP3) were identified for the first time to be related to AD susceptibility. Our study identified novel genes and splicing introns associated with AD risk, which can improve our understanding of the etiology of AD.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. Inthe testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI= 0.635-0.677) in African and 0.844 (95%CI=0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI= 1.67-2.00) and 2.19 (95% CI= 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC= 0.679, 95% CI= 0.659-0.700 and AUC= 0.845, 95% CI= 0.841-0.849, respectively) and comparable prostate cancer ORs (OR= 2.05, 95% CI= 1.87-2.26 and OR= 2.21, 95% CI= 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Ischemic Stroke and Cerebral Microbleeds: A Two-Sample Bidirectional Mendelian Randomization Study.

Recent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs. The summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association. We detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04-2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07-2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes. Our study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.

Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study.

Background: Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. Methods: To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Results: Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, p = 1.2 × 10-5), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, p = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, p = 8.0 × 10-6). Conclusion: Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.

Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights

BackgroundGenomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. ObjectiveTo identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. Design, setting, and participantsData from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. Outcome measurements and statistical analysesLog-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. Results and limitationsMultiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10−8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44–1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. ConclusionsWe report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. Patient summaryWe identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.

Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population

High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. Here, we report a whole-exome sequencing (WES) study in 9,613 HM cases and 9,606 controls of Han Chinese ancestry to pinpoint HM-associated risk variants. Single-variant association analysis identified three newly identified -genetic loci associated with HM, including an East Asian ancestry-specific low-frequency variant (rs533280354) in FKBP5. Multi-ancestry meta-analysis with WES data of 2,696 HM cases and 7,186 controls of European ancestry from the UK Biobank discerned a newly identified European ancestry-specific rare variant in FOLH1. Functional experiments revealed a mechanism whereby a single G-to-A transition at rs533280354 disrupted the binding of transcription activator KLF15 to the promoter of FKBP5, resulting in decreased transcription of FKBP5. Furthermore, burden tests showed a significant excess of rare protein-truncating variants among HM cases involved in retinal blood vessel morphogenesis and neurotransmitter transport.

Abstract LB045: Transcriptome-wide association study identifies susceptibility loci and genes for lung cancer risk

Abstract Objective: Genome-wide association studies (GWAS) have identified more than 50 loci for lung cancer risk. However, susceptibility genes and the underlying mechanisms for these risk loci remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify susceptibility genes for lung cancer. Methods: Transcriptome data from normal lung tissue and whole-genome sequencing data from 444 participants of European ancestry in the Genotype-Tissue Expression (GTEx, version 8) were used to build lung-tissue models to predict gene expression levels. Lung-tissue prediction models were successfully established for 10,802 genes with a model performance r &amp;gt; 0.1 and P &amp;lt; 0.05. We also built joint-tissue models using the joint-tissue imputation (JTI) framework, which leverages transcriptome data from lung tissue and 48 other tissue types from the 444 participants in GTEx. Joint-tissue models were successfully established for 12,629 genes with a model performance r &amp;gt; 0.1 and P &amp;lt; 0.05. These prediction models were applied to the GWAS data comprised of 29,266 lung cancer cases and 56,450 controls of European ancestry, in order to evaluate genetically predicted gene expression levels in association with lung cancer risk. Results: We found 44 genes whose genetically predicted expression levels were significantly associated with overall lung cancer risk at the Bonferroni correction significance threshold. Among the 44 genes, four were located at least 500kb away from any of the leading variants identified previously in GWAS. Of these four genes, only the CCHCR1 gene has been reported in previous TWAS, and the other three genes, LY6G5B, PRSS16, and C19orf54, have never been reported in previous GWAS or TWAS. For each of these three novel genes, consistent associations were observed in both lung-tissue and joint-tissue models. For the 40 genes located in previously identified GWAS loci, after adjusting for GWAS-identified variants, the associations for the majority of them became non-significant. However, the associations did not change materially for UCKL1 or PRPF6. These results suggest that the associations for these two genes were independent from previous GWSA-identified signals. We also identified 10 genes located at least 500kb away from GWAS-identified loci that were associated with lung cancer histological subtypes, e.g., adenocarcinoma (DCBLD1 and AQP3), squamous cell carcinoma (ZSCAN26, BLOC1S2, ABCF1, and ZSCAN9), and small cell lung cancer (BTN2A2, TMA16, RP11-218F10.3, and FRS3). An additional 7 genes located in GWAS loci were associated with risk of lung cancer histological subtypes but not with overall lung cancer risk, including 4 genes for adenocarcinoma (TP63, STN1, FAM227B, and TPRG1) and 3 genes for squamous cell carcinoma (DDAH2, OR2H2, and NELFE). Conclusion: Our TWAS identified lung cancer susceptibility genes, providing new insight into the genetics of lung cancer etiology. Citation Format: Tianying Zhao, Jiajun Shi, Yaohua Yang, Jie Ping, Xiao Ou Shu, Wei Zheng, Jirong Long, Qiuyin Cai. Transcriptome-wide association study identifies susceptibility loci and genes for lung cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB045.

Abstract 1180: Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data

Abstract Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) &amp;lt;0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR &amp;lt;0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-kB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk. Citation Format: Guochong Jia, Yaohua Yang, Jie Ping, Shuai Xu, Lili Liu, Xingyi Guo, Ran Tao, Jirong Long, Wei Zheng. Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1180.

Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data.

Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1142 circulating proteins with breast cancer risk in 133 384 cases and 113 789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500 kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk.

Mendelian Randomization Study on Causal Association of IL-6With Breast Cancer

BackgroundPrevious studies have shown an important role of interleukin 6 (IL-6) in the progression and metastasis of breast cancer. The present 2-sample Mendelian randomization (MR) study aimed to identify the genetic causal link between IL-6 and breast cancer. Material and MethodsIL-6-signaling and its negative regulator soluble IL-6 receptor (sIL-6R) genetic instruments were chosen from 2 large-scale genome-wide association studies (GWAS) of 204,402 and 3,301 European individuals, respectively. GWAS for breast cancer (14,910 cases and 17,588 controls of European ancestry) was used to evaluate the effect of IL-6-signaling- or sIL-6R-associated genetic instrumental variants on breast cancer risk by performing a 2-sample MR study. ResultsAs IL-6-signaling genetically increased, breast cancer risk increased based on weighted median (odds ratio [OR] = 1.396, 95% confidence interval [CI]: 1.008-1.934, P = .045) and inverse variance weighted (IVW) (OR = 1.370, 95% CI: 1.032-1.819, P = .030). Otherwise, as sIL-6R genetically increased, the risk of breast cancer decreased based on weighted median (OR = 0.975, 95% CI: 0.947-1.004, P = .097) and IVW (OR = 0.977, 95% CI: 0.956-0.997, P = .026). ConclusionOur analysis suggests a causal link between a genetically-linked increase in IL-6-signaling and increase in the risk of breast cancer. Thus, inhibition of IL-6 may be a valuable biological indicator for risk assessment, prevention, and treatment of patients with breast cancer.