scholarly journals Mendelian randomisation study of smoking exposure in relation to breast cancer risk

2021 ◽  
Author(s):  
Hanla A. Park ◽  
Sonja Neumeyer ◽  
Kyriaki Michailidou ◽  
Manjeet K. Bolla ◽  
Qin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Smoking Exposure

Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 1029-1031 ◽  
Author(s):  
Yussanne P. Ma ◽  
Flora E. van Leeuwen ◽  
Rosie Cooke ◽  
Annegien Broeks ◽  
Victor Enciso-Mora ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Hodgkin Lymphoma ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Control Series ◽  
Cancer Risk Factors ◽  
Increased Risk

Abstract Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

scholarly journals Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoxin Peng ◽  
Xiangrong Wu ◽  
Yaokai Wen ◽  
Yiyuan Ao ◽  
Yutian Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Computer Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sedentary Behaviors ◽  
Watching Tv

Background:Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown.Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality.Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44–2.50; p < 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31–2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12–2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44–2.68; p < 0.001) and body mass index (OR, 1.86; 95%CI, 1.36–2.54; p < 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287–1.884; p < 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004–1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality.Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

scholarly journals Chromatin interactome mapping at 139 independent breast cancer risk signals

2019 ◽  
Author(s):  
Jonathan Beesley ◽  
Haran Sivakumaran ◽  
Mahdi Moradi Marjaneh ◽  
Luize G. Lima ◽  
Kristine M. Hillman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Target Genes ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Breast Cancer Cell Lines ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Candidate Target

ABSTRACTGenome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals, and explore the functional mechanism underlying altered risk at the 12q24 risk region. Our results demonstrate the power of combining genetics, computational genomics and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

Cigarette smoking and schizophrenia: Mendelian randomisation study

2020 ◽  
pp. 1-6
Author(s):  
Jianhua Chen ◽  
Ruirui Chen ◽  
Siying Xiang ◽  
Ningning Li ◽  
Chengwen Gao ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Association Studies ◽  
Smoking Initiation ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Complex Behaviour ◽  
Asian Populations ◽  
Smoking Behaviours

Background The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause–effect relationship remains unclear. Aims We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia. Method We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results. Results The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results. Conclusions Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.

scholarly journals The association between weight at birth and breast cancer risk revisited using Mendelian randomisation

2018 ◽  
Author(s):  
Siddhartha P. Kar ◽  
Irene L. Andrulis ◽  
Hermann Brenner ◽  
Stephen Burgess ◽  
Jenny Chang-Claude ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Adult Life ◽  
Data Availability ◽  
Alternative Methods ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Age At Menarche ◽  
Increased Risk

AbstractObservational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval: 0.73—1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer. Thus, there is little evidence from MR to suggest that the previously observed association between higher BW and increased risk of breast cancer in adult life is causal.

scholarly journals 586Effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation analysis

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Jian Zhao ◽  
Rachel Freathy ◽  
David Evans ◽  
Nicole Warrington ◽  
Claudia Langenberg ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Association Studies ◽  
Amino Acid Level ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Reverse Causality

Abstract Background It is suggested amino acids are critical for fetal growth, but analyses assessing causality are lacking. Mendelian randomisation (MR) can be used to examine causal effects under instrumental variable (IV) assumptions. Methods We conducted a two-sample MR study utilizing summary data from genome-wide association studies (GWAS) of amino acids (sample 1, n = 86,507) and of offspring birthweight (sample 2, combined UK Biobank and Early Growth Genetics Consortium, n = 406,063). Seventy-five independent single nucleotide polymorphisms (SNPs) robustly associated with 18 amino acids (p &lt; 4.9 × 10-10) were used as genetic instruments. Wald ratio and inverse variance weighted methods were used in MR main analysis. Sensitivity analyses were performed to explore IV assumption violations. To explore whether there was consistency between SNP-amino acid associations in pregnancy and in the GWAS, the latter were compared to associations in the Born in Bradford cohort. Results There was evidence of positive causal effects of maternal alanine (51.9 g birthweight increase per SD increase in amino acid level, 95% CI: 24.2, 79.5), glutamine (51.3 g, 95% CI: 33.5, 69.0), glycine (10.4 g, 95% CI: 1.3, 19.6) and serine (27.1 g, 95% CI: 11.2, 43.0) on birthweight and inverse causal effects of maternal isoleucine (-109.7 g, 95% CI: -194.6, -24.9) and histidine (-41.1 g, 95% CI: -78.5, -3.7) on birthweight. Sensitivity analyses to explore reverse causality and bias due to horizontal pleiotropy supported our findings. Conclusions Some maternal circulating amino acids have causal effects on birthweight. Key messages MR can be extended to probe effects of maternal nutrition on offspring development.

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