Causal Effect of Serum Magnesium on Osteoporosis and Cardiometabolic Diseases

Serum magnesium is associated with osteoporosis and cardiometabolic diseases, but their causal associations remain elusive. We used the two-sample Mendelian randomization (MR) study to explore the causal roles of serum magnesium on osteoporosis and cardiometabolic diseases by using the aggregated genome-wide association studies (GWASs). Six single-nucleotide polymorphisms (SNPs, p < 5 × 10−8) associated with serum magnesium concentrations were all used as instrumental variables. A genetic predisposition to higher serum magnesium concentrations was inversely associated with lower lumbar spine bone mineral density (BMD, beta-estimate: −1.982, 95% CI: −3.328 to −0.635, SE: 0.687, p = 0.004), which was further confirmed by multiple sensitivity analyses. There was limited evidence of associations between serum magnesium and type 2 diabetes, coronary artery disease, heart failure, and atrial fibrillation. This work provided strong evidence that genetically increased serum magnesium concentrations were causally associated with low lumbar spine BMD and suggested that serum magnesium concentrations may be crucial to prevent osteoporosis.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.742718 ◽

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.

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

British Journal of Cancer ◽

10.1038/s41416-021-01432-8 ◽

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.

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Depression and Osteoporosis: A Mendelian Randomization Study

Calcified Tissue International ◽

10.1007/s00223-021-00886-5 ◽

2021 ◽

Author(s):

Bin He ◽

Qiong Lyu ◽

Lifeng Yin ◽

Muzi Zhang ◽

Zhengxue Quan ◽

...

Keyword(s):

Observational Studies ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Meta Analysis ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Reverse Causality ◽

Mineral Density

AbstractObservational studies suggest a link between depression and osteoporosis, but these may be subject to confounding and reverse causality. In this two-sample Mendelian randomization analysis, we included the large meta-analysis of genome-wide association studies for depression among 807,553 individuals (246,363 cases and 561,190 controls) of European descent, the large meta-analysis to identify genetic variants associated with femoral neck bone mineral density (FN-BMD), forearm BMD (FA-BMD) and lumbar spine BMD (LS-BMD) among 53,236 individuals of European ancestry, and the GWAS summary data of heel BMD (HE-BMD) and fracture among 426,824 individuals of European ancestry. The results revealed that genetic predisposition towards depression showed no causal effect on FA-BMD (beta-estimate: 0.091, 95% confidence interval [CI] − 0.088 to 0.269, SE:0.091, P value = 0.320), FN-BMD (beta-estimate: 0.066, 95% CI − 0.016 to 0.148, SE:0.042, P value = 0.113), LS-BMD (beta-estimate: 0.074, 95% CI − 0.029 to 0.177, SE:0.052, P value = 0.159), HE-BMD (beta-estimate: 0.009, 95% CI − 0.043 to 0.061, SE:0.027, P value = 0.727), or fracture (beta-estimate: 0.008, 95% CI − 0.071 to 0.087, SE:0.041, P value = 0.844). These results were also confirmed by multiple sensitivity analyses. Contrary to the findings of observational studies, our results do not reveal a causal role of depression in osteoporosis or fracture.

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Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

International Journal of Epidemiology ◽

10.1093/ije/dyaa266 ◽

2021 ◽

Author(s):

Fernando Pires Hartwig ◽

Kate Tilling ◽

George Davey Smith ◽

Deborah A Lawlor ◽

Maria Carolina Borges

Keyword(s):

Waist Circumference ◽

Genetic Variants ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Real Data ◽

Sensitivity Analyses ◽

Effect Estimate ◽

Genome Wide Association Studies ◽

Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

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Cigarette smoking and schizophrenia: Mendelian randomisation study

The British Journal of Psychiatry ◽

10.1192/bjp.2020.116 ◽

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.

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Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density

10.1101/2021.07.01.21259826 ◽

2021 ◽

Author(s):

Daniel Schmitz ◽

Weronica E Ek ◽

Elin Berggren ◽

Julia Höglund ◽

Torgny Karlsson ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Causal Effect ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Mineral Density ◽

Skeletal Health ◽

Genome Wide ◽

Estradiol Levels

Context. Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. Objective. Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). Design. We performed GWAS for estradiol in males (N = 147,690) and females (N = 163,985) from UK Biobank (UKB). Estradiol was analyzed as a binary phenotype; above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. Results. We identified 14 independent loci associated (P<5x10-8) with estradiol levels in males, of which one (CYP3A7) was genome-wide and seven nominally (P<0.05) significant in females. In addition, one female specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS. For example, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7 which encode enzymes likely to be involved in estradiol elimination. The allele that tags the O blood group, at the ABO locus, was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P=1.58x10-11) and females (P=7.48x10-6). Conclusion. Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.

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

International Journal of Epidemiology ◽

10.1093/ije/dyab168.757 ◽

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 < 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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Transcription Factor Enrichment Analysis in Enhancers Identifies EZH2 as a Susceptibility Gene for Osteoporosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz270 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1152-e1161

Author(s):

Meng Li ◽

Shi Yao ◽

Yuan-Yuan Duan ◽

Yu-Jie Zhang ◽

Yan Guo ◽

...

Keyword(s):

Chinese Population ◽

Multiple Testing ◽

Association Studies ◽

Susceptibility Gene ◽

Enrichment Analysis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

Association Analyses ◽

Hip Bmd

Abstract Purpose Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with osteoporosis. Most of these SNPs are noncoding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs; thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis. Methods We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. Results After functional annotation, a total of 5081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = .028) and NRSF (Padj = .038). We also found 1 SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32 × 10–4; spine BMD: P = 2.72 × 10–3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice. Conclusions By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis.

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Genetically proxied morning chronotype was associated with a reduced risk of prostate cancer

SLEEP ◽

10.1093/sleep/zsab104 ◽

2021 ◽

Author(s):

Xiaohui Sun ◽

Ding Ye ◽

Mengting Jiang ◽

Yu Qian ◽

Yingying Mao

Keyword(s):

Prostate Cancer ◽

Causal Effect ◽

Association Studies ◽

Meta Analysis ◽

Prostate Cancer Risk ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Primary Analysis ◽

Weighted Median ◽

Reduced Risk

Abstract Study Objectives Observational epidemiological studies have suggested that chronotype may play a role in the pathogenesis and progression of prostate cancer. However, whether there is a causal association remains unknown. The aim of the present study was to examine the potential causal relationship between chronotype and prostate cancer risk using a Mendelian randomization (MR) design. Methods A total of 268 single nucleotide polymorphisms associated with chronotype were selected from a meta-analysis of genome-wide association studies of 697,828 individuals. The genetic association data for prostate cancer was derived from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) Consortium (79,148 cases and 61,106 controls). Inverse-variance-weighted (IVW) method was used as the primary analysis to calculate the causal effect estimates. The weighted-median method, MR-Egger regression, MR-PRESSO test, and multivariable MR analyses were applied as sensitivity analysis. Results Genetically predicted morningness (scaled to a sleep midpoint of 1 hour earlier) had a reduced risk of prostate cancer, with an odds ratio of 0.71 (95% confidence interval (CI): 0.54-0.94 by IVW), compared with the eveningness. Similar causal effect estimates were also observed by using the weighted median and MR-PRESSO analyses. In addition, results from the multivariable MR analysis supported the findings from the univariable MR analyses. No indication of horizontal pleiotropy was observed in the MR-Egger analysis (P for intercept =0.234). Conclusion Our findings provide evidence of a causal protective effect of morning chronotype on the risk of prostate cancer.

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Identification of New Genes and Loci Associated With Bone Mineral Density Based on Mendelian Randomization

Frontiers in Genetics ◽

10.3389/fgene.2021.728563 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yijun Liu ◽

Guang Jin ◽

Xue Wang ◽

Ying Dong ◽

Fupeng Ding

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Rare Variants ◽

Mendelian Randomization ◽

Association Studies ◽

Osteoporotic Fractures ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

New Genes

Bone mineral density (BMD) is a complex and highly hereditary trait that can lead to osteoporotic fractures. It is estimated that BMD is mainly affected by genetic factors (about 85%). BMD has been reported to be associated with both common and rare variants, and numerous loci related to BMD have been identified by genome-wide association studies (GWAS). We systematically integrated expression quantitative trait loci (eQTL) data with GWAS summary statistical data. We mainly focused on the loci, which can affect gene expression, so Summary data-based Mendelian randomization (SMR) analysis was implemented to investigate new genes and loci associated with BMD. We identified 12,477 single-nucleotide polymorphisms (SNPs) regulating 564 genes, which are associated with BMD. The genetic mechanism we detected could make a contribution in the density of BMD in individuals and play an important role in understanding the pathophysiology of cataclasis.

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