Association between depression and sleep apnoea: a Mendelian randomisation study

BackgroundStudies have reported a close relationship between depression and sleep apnoea, yet it is unknown whether these are causally related. Thus, we aimed to determine whether depression is associated with the aetiology of sleep apnoea.MethodsWe used publicly available genetic summary data from two large consortia, the Psychiatric Genomics Consortium, with data from 36 single-nucleotide polymorphisms (SNPs) closely associated with major depressive disorder (MDD) and UK Biobank, including 456 736 patients with sleep apnoea and 766 964 controls. For Mendelian randomisation (MR) analysis, we used the inverse-variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum, and outlier test to retrieve summary data. Analyses were performed using the “TwoSampleMR” package in R.ResultsOf the 36 SNPs associated with MDD, we found statistically significant evidence of a potential causal effect of MDD on the risk of sleep apnoea (odds ratio 1.004, 95% confidence interval: 1.001–1.006, p=0.001). Similar results were obtained using the MR-Egger and weighted median methods. Additionally, we found no heterogeneity or pleiotropy.ConclusionsOur findings suggest that depression slightly increases the risk of sleep apnoea. Further investigation of the potential biological mechanisms is necessary.

Download Full-text

Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa506 ◽

2020 ◽

Author(s):

Yi-Lin Dan ◽

Peng Wang ◽

Zhongle Cheng ◽

Qian Wu ◽

Xue-Rong Wang ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Effects ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P < 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

Download Full-text

Elucidation of a Causal Relationship Between Platelet Count and Hypertension: A Bi-Directional Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.743075 ◽

2021 ◽

Vol 8 ◽

Author(s):

Po-Chun Chiu ◽

Amrita Chattopadhyay ◽

Meng-Chun Wu ◽

Tzu-Hung Hsiao ◽

Ching-Heng Lin ◽

...

Keyword(s):

Platelet Count ◽

Causal Relationship ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Exact Nature ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Hypertension has been reported as a major risk factor for diseases such as cardiovascular disease, and associations between platelet activation and risk for hypertension are well-established. However, the exact nature of causality between them remains unclear. In this study, a bi-directional Mendelian randomization (MR) analysis was conducted on 15,996 healthy Taiwanese individuals aged between 30 and 70 years from the Taiwan Biobank, recorded between 2008 and 2015. The inverse variance weighted (IVW) method was applied to determine the causal relationship between platelet count and hypertension with single nucleotide polymorphisms as instrumental variables (IVs). Furthermore, to check for pleiotropy and validity of the IVs, sensitivity analyses were performed using the MR-Egger, weighted median and simple median methods. This study provided evidence in support of a positive causal effect of platelet count on the risk of hypertension (odds ratio: 1.149, 95% confidence interval: 1.131–1.578, P < 0.05), using the weighted median method. A significant causal effect of platelet count on hypertension was observed using the IVW method. No pleiotropy was observed. The causal effect of hypertension on platelet count was found to be non-significant. Therefore, the findings from this study provide evidence that higher platelet count may have a significant causal effect on the elevated risk of hypertension for the general population of Taiwan.

Download Full-text

Pediatric and Adult Obesity Concern Female Health: A Mendelian Randomization Study

10.21203/rs.3.rs-390994/v1 ◽

2021 ◽

Author(s):

yishang yan ◽

Zihao Qu ◽

Ping-ping Lv ◽

He-Feng Huang

Keyword(s):

Mendelian Randomization ◽

Later Life ◽

Nucleotide Polymorphisms ◽

Adult Obesity ◽

Gynecological Cancers ◽

Single Nucleotide ◽

Genetic Groups ◽

Inverse Variance ◽

Children Obesity ◽

Weighted Median

Abstract Purpose: Adulthood and childhood obesity are associated with female reproductive endocrinology and gynecological cancers. However, the causality of such association is yet to be identified. Independent of inverse bias and confounding, mendelian randomization is like a random control trial where genetic groups are settled during meiosis, which could be effective to examine the causality. Methods: We carried out several Mendelian randomization trials based on combined genetic scores of 75 adult-associated and 15 child-associated BMI single nucleotide polymorphisms (SNPs), diseases databases of several gynecological cancers and reproductive diseases from UK Biobank with 194,153 participants, using traditional inverse-variance weighted (IVW) method, Weighted Median (WM) approach, MR-Egger regression and updated MR-PRESSO analysis. Results: Elevated adult-associated BMI (effect:1.003;95%CI:1.001,1.004) and child-associated BMI (effect:1.003;95%CI:1.001,1.004) genetic scores were related to higher risk of PCOS incidence by using traditional IVW method. Random IVW method showed a negative causal association between the child-associated BMI and subsequent endometriosis attack(effect:0.995;95%CI:0.991,0.999). Conclusions: Consistent with observational consequences, our findings suggested that childhood and adulthood obesity may play roles in the development of PCOS, and children obesity can elevate the possibility of PCOS but decrease the incidence of endometriosis in later life. More researches need to be conducted for further validation and potential mechanisms.

Download Full-text

Robust inference in summary data Mendelian randomisation via the zero modal pleiotropy assumption

10.1101/126102 ◽

2017 ◽

Cited By ~ 14

Author(s):

Fernando Pires Hartwig ◽

George Davey Smith ◽

Jack Bowden

Keyword(s):

Instrumental Variable ◽

Causal Effect ◽

Association Studies ◽

Mendelian Randomisation ◽

Effect Estimate ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Weighted Median ◽

Summary Data ◽

Genetic Instruments

AbstractBackgroundMendelian randomisation (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions.MethodsHere, a new method –the mode-based estimate (MBE) – is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk.ResultsThe MBE presented less bias and type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared to the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia.ConclusionsThe MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in a sensitivity analysis.Key MessagesSummary data Mendelian randomisation, typically in a two-sample setting, is being increasingly used due to the availability of summary association results from large genome- wide association studies.Mendelian randomisation analyses using multiple genetic instruments are prone to bias due to horizontal pleiotropy, especially when genetic instruments are selected based solely on statistical criteria.A causal effect estimate robust to horizontal pleiotropy can be obtained using the mode- based estimate (MBE).The MBE requires that the most common causal effect estimate is a consistent estimate of the true causal effect, even if the majority of instruments are invalid (i.e., the ZEro Modal Pleiotropy Assumption, or ZEMPA).Plotting the smoothed empirical density function is useful to explore the distribution of causal effect estimates, and to understand how the MBE is determined.

Download Full-text

Assessing the Causality Factors in the Association between (Abdominal) Obesity and Physical Activity among the Newfoundland Population–-A Mendelian Randomization Analysis

Genetics & Epigenetics ◽

10.4137/geg.s38289 ◽

2016 ◽

Vol 8 ◽

pp. GEG.S38289 ◽

Cited By ~ 2

Author(s):

Frank Barning ◽

Taraneh Abarin

Keyword(s):

Physical Activity ◽

Newfoundland And Labrador ◽

Mendelian Randomization ◽

Causal Effect ◽

Intervention Strategies ◽

Nucleotide Polymorphisms ◽

Fto Gene ◽

Single Nucleotide ◽

Similar Association ◽

Randomization Analysis

A total of 1,263 adults from Newfoundland and Labrador were studied in the research. Body mass index (BMI) and percent trunk fat (PTF) were analyzed as biomarkers for obesity. The Mendelian randomization (MR) approach with two single-nucleotide polymorphisms in the fat-mass and obesity (FTO) gene as instruments was employed to assess the causal effect. In both genders, increasing physical activity significantly reduced BMI and PTF when adjusted for age and the FTO gene. The effect of physical activity was stronger on PTF than BMI. Direct observational analyses showed significant increase in BMI/PTF when physical activity decreased. A similar association in MR analyses was not significant. The association between physical activity and BMI/PTF could be due to reversed causality or common confounding factors. Our study provides insights into the causal contributions of obesity to physical activity in adults. Health intervention strategies to increase physical activity among adults should include some other plans such as improving diet for reducing obesity.

Download Full-text

Serum Iron Status and the Risk of Breast Cancer in Europeans: A 2-Sample Mendelian Randomisation Study

10.21203/rs.3.rs-57485/v1 ◽

2020 ◽

Author(s):

Chenyang Hou ◽

Qingzhi Hou ◽

Xing Xie ◽

Huifeng Wang ◽

Yueliang Chen ◽

...

Keyword(s):

Breast Cancer ◽

Instrumental Variables ◽

Serum Iron ◽

Iron Status ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Simple Mode ◽

Inverse Variance ◽

Liberal Approach ◽

Mr Study

Abstract Background: Previous observational studies showed that there was a conflict about serum iron status and the risk of breast cancer, which could have an impact on the prevention of breast cancer.Object: We used a two sample Mendelian randomisation (MR) study to explore the causal relationship between iron status and the risk of breast cancer.Method: To select single nucleotide polymorphisms (SNPs) which could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium. Moreover, we used the OncoArray network to select SNPs of instrumental variables for the outcome (breast cancer). The conservative instruments (SNPs were all consistent with iron status) and liberal instruments (SNPs was associated with at least one of iron status) were used in MR analysis. In the conservative instruments set we used an inverse-variance weighted (IVW) approach, and in the liberal instruments set we used the IVW, MR-Egger regression, weighted median and simple mode approach. Results: In the conservative approach, none of the iron status were statistically significant for breast cancer or its subtypes. And in the liberal approach, transferrin was positively associated with ER-negative breast cancer by simple mode (OR for MR: 1.225; 95% CI: 1.064, 1.410; P=0.030). However, other iron statuses had no association with breast cancer or its subtypes (P>0.05).Conclusion: Our MR study, in the liberal approach, suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, and other iron statuses had no effect on breast cancer or its subtypes. This could be verified in future studies.

Download Full-text

1202. Multimodal Sequencing of a Clonal Case Cluster of Carbapenem-Resistant Citrobacter Reveals Unexpectedly Rapid Dynamics of KPC3-Containing Plasmids

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1035 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S364-S364

Author(s):

Roby Bhattacharyya ◽

Alejandro Pironti ◽

Bruce J Walker ◽

Abigail Manson ◽

Virginia Pierce ◽

...

Keyword(s):

Point Mutations ◽

Illumina Miseq ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Single Nucleotide ◽

Carbapenem Resistant ◽

Oxford Nanopore ◽

Close Relationship ◽

Long Read ◽

Carbapenem Resistant Enterobacteriaceae

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) are a major public health threat. We report four clonally related Citrobacter freundii isolates harboring the blaKPC-3 carbapenemase in April–May 2017 that are nearly identical to a strain from 2014 at the same institution. Despite differing by ≤5 single nucleotide polymorphisms (SNPs), these isolates exhibited dramatic differences in carbapenemase plasmid architecture. Methods We sequenced four carbapenem-resistant C. freundii isolates from 2017 and compared them with an ongoing CRE surveillance project at our institution. SNPs were identified from Illumina MiSeq data aligned to a reference genome using the variant caller Pilon. Plasmids were assembled from Illumina and Oxford Nanopore sequencing data using Unicycler. Results The four 2017 isolates differed from one another by 0–5 chromosomal SNPs; two were identical. With one exception, these isolates differed by >38,000 SNPs from 25 C. freundii isolates sequenced from 2013 to 2017 at the same institution for CRE surveillance. The exception was a 2014 isolate that differed by 13–16 SNPs from each 2017 isolate, with 13 SNPs common to all four. Each C. freundii isolate harbored wild-type blaKPC-3. Despite the close relationship among the 2017 cluster, the plasmids harboring the blaKPC-3 genes differed dramatically: the carbapenemase occurred in one of the two different plasmids, with rearrangements between these plasmids across isolates. The related 2014 isolate harbored both plasmids, each with a separate copy of blaKPC-3. No transmission chains were found between any of the affected patients. Conclusion WGS confirmed clonality among four contemporaneous blaKPC-3-containing C. freundii isolates, and marked similarity with a 2014 isolate, within an institution. That only 13–16 SNPs varied between the 2014 and 2017 isolates suggests durable persistence of the blaKPC-3 gene within this lineage in a hospital ecosystem. The plasmids harboring these carbapenemase genes proved remarkably plastic, with plasmid loss and rearrangements occurring on the same time scale as two to three chromosomal point mutations. Combining short and long-read sequencing in a case cluster uniquely revealed unexpectedly rapid dynamics of carbapenemase plasmids, providing critical insight into their manner of spread. Disclosures M. J. Ferraro, SeLux Diagnostics: Scientific Advisor and Shareholder, Consulting fee. D. C. Hooper, SeLux Diagnostics: Scientific Advisor, Consulting fee.

Download Full-text

GrgA as a potential target of selective antichlamydials

10.1101/437285 ◽

2018 ◽

Author(s):

Huirong Zhang ◽

Sangeevan Vellappan ◽

M. Matt Tang ◽

Xiaofeng Bao ◽

Huizhou Fan

Keyword(s):

Adverse Effects ◽

Causal Effect ◽

Reproductive Age ◽

Host Cells ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Low Level ◽

Prophylactic Measures ◽

Susceptibility Tests ◽

Necessary And Sufficient

ABSTRACTChlamydiais a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rareChlamydiavariant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, theChlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance inChlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.

Download Full-text

Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study

European Respiratory Journal ◽

10.1183/13993003.00329-2018 ◽

2018 ◽

Vol 51 (6) ◽

pp. 1800329 ◽

Cited By ~ 4

Author(s):

Yi-Qian Sun ◽

Ben M. Brumpton ◽

Carolina Bonilla ◽

Sarah J. Lewis ◽

Stephen Burgess ◽

...

Keyword(s):

Lung Cancer ◽

Cohort Study ◽

Population Based ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Hydroxyvitamin D ◽

Inverse Variance ◽

25 Hydroxyvitamin D ◽

Histologic Types ◽

Genetically Determined

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93–1.06) per allele score. A 25 nmol·L−1increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54–1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

Download Full-text

Using Mendelian randomisation to assess causality in observational studies

Evidence-Based Mental Health ◽

10.1136/ebmental-2019-300085 ◽

2019 ◽

Vol 22 (2) ◽

pp. 67-71 ◽

Cited By ~ 3

Author(s):

Panagiota Pagoni ◽

Niki L Dimou ◽

Neil Murphy ◽

Evie Stergiakouli

Keyword(s):

Statistical Methods ◽

Causal Effects ◽

Likelihood Method ◽

Mendelian Randomisation ◽

Research Assessment ◽

Ratio Estimator ◽

Inverse Variance ◽

Weighted Median ◽

Median Approach ◽

The Impact

ObjectiveMendelian randomisation (MR) is a technique that aims to assess causal effects of exposures on disease outcomes. The paper aims to present the main assumptions that underlie MR, the statistical methods used to estimate causal effects and how to account for potential violations of the key assumptions.MethodsWe discuss the key assumptions that should be satisfied in an MR setting. We list the statistical methodologies used in two-sample MR when summary data are available to estimate causal effects (ie, Wald ratio estimator, inverse-variance weighted and maximum likelihood method) and identify/adjust for potential violations of MR assumptions (ie, MR-Egger regression and weighted Median approach). We also present statistical methods and graphical tools used to evaluate the presence of heterogeneity.ResultsWe use as an illustrative example of a published two-sample MR study, investigating the causal association of body mass index with three psychiatric disorders (ie, bipolar disorder, schizophrenia and major depressive disorder). We highlight the importance of assessing the results of all available methods rather than each method alone. We also demonstrate the impact of heterogeneity in the estimation of the causal effects.ConclusionsMR is a useful tool to assess causality of risk factors in medical research. Assessment of the key assumptions underlying MR is crucial for a valid interpretation of the results.

Download Full-text