Causal Effects of Homocysteine, Folate, and Cobalamin on Kidney Function: A Mendelian Randomization Study

Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change −0.95 (−1.21, −0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (−0.11 (−0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.

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Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study

10.1101/2021.01.29.21250759 ◽

2021 ◽

Author(s):

Bonnie K Patchen ◽

Andrew G Clark ◽

Dana B Hancock ◽

Nathan Gaddis ◽

Patricia A Cassano

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Mendelian Randomization ◽

Serum Vitamin ◽

Causal Effects ◽

European Ancestry ◽

Vitamin D Metabolism ◽

Serum Vitamin D ◽

Genome Wide ◽

Population Controls

ABSTRACTObjectivesTo investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.DesignTwo-sample Mendelian randomization study.SettingSummary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analyzed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.Participants17,965 COVID-19 cases including 11,085 laboratory or physician confirmed cases, 7,885 hospitalized cases, and 4,336 severe respiratory cases, and 1,370,547 controls, primarily of European ancestry.ExposuresGenetically predicted variation in serum vitamin D status, based on genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.Main outcome measuresSusceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalization.ResultsMendelian randomization analysis, powered to detect moderate effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as proxies for serum vitamin D concentration, the odds ratio for a standard deviation increase in serum vitamin D was 1.04 (95% confidence interval 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84-1.31) for hospitalized COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative, and 1.44 (0.75 to 2.78) for hospitalized COVID-19 versus non-hospitalized COVID-19. Results were similar in analyses that used all SNPs with genome-wide significant associations with serum vitamin D (i.e., including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.ConclusionsThese findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects, nor do they preclude potential causal effects of acute responses to therapeutic doses of vitamin D. Future directions include extension of this work to non-European ancestry populations, and high-risk populations, for example persons with comorbid disease.

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Causal Effects of Positive Affect, Life Satisfaction, Depressive Symptoms, and Neuroticism on Kidney Function: A Mendelian Randomization Study

Journal of the American Society of Nephrology ◽

10.1681/asn.2020071086 ◽

2021 ◽

pp. ASN.2020071086 ◽

Cited By ~ 1

Author(s):

Sehoon Park ◽

Soojin Lee ◽

Yaerim Kim ◽

Yeonhee Lee ◽

Min Woo Kang ◽

...

Keyword(s):

Life Satisfaction ◽

Depressive Symptoms ◽

Confidence Interval ◽

Positive Affect ◽

Kidney Function ◽

Mendelian Randomization ◽

Causal Effects ◽

European Ancestry ◽

Uk Biobank ◽

Lower Egfr

BackgroundFurther investigation of the causal effects of psychologic wellbeing on kidney function is warranted.MethodsIn this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry (n=567,460), and additional allele score–based MR was performed in the individual-level data of White British UK Biobank participants (n=321,024).ResultsIn summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta −2.18; 95% confidence interval, −3.61 to −0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD.ConclusionsHealth care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function.

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Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity

Frontiers in Genetics ◽

10.3389/fgene.2021.762697 ◽

2022 ◽

Vol 12 ◽

Author(s):

Li-Juan Qiu ◽

Kang-Jia Yin ◽

Gui-Xia Pan ◽

Jing Ni ◽

Bin Wang

Keyword(s):

Severe Asthma ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Severe Disease ◽

Causal Effects ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide ◽

Inverse Variance ◽

Increased Risk

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity.Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted.Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses.Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

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Genetic Determinants of Blood Cell Traits Play a Role in Susceptibility to Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2020-141443 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Linda Kachuri ◽

Soyoung Jeon ◽

Andrew T. DeWan ◽

Catherine Metayer ◽

John S. Witte ◽

...

Keyword(s):

Blood Cell ◽

Lymphoblastic Leukemia ◽

Causal Effects ◽

European Ancestry ◽

Trait Variation ◽

Cell Counts ◽

Snp Data ◽

Genetic Predictors ◽

Genome Wide ◽

Genetic Instruments

Background: Genome-wide association studies (GWAS) have identified several genes associated with childhood acute lymphoblastic leukemia (ALL) that are also implicated in variation in hematological traits. We performed a comprehensive study of the shared heritability of blood cell traits and ALL, and investigated whether genetic variation in blood cell traits may underlie ALL risk. Methods: We leveraged genome-wide single nucleotide polymorphism (SNP) data from: 1) 335,332 European ancestry, cancer-free subjects without immune deficiencies or hematopoietic disorders in the UK Biobank (UKB); and 2) a childhood ALL GWAS meta-analysis including 2,121 cases and 59,965 controls of European ancestry, to investigate the shared genetic basis of blood cell trait variation and ALL susceptibility. Co-heritability between blood cell profiles and ALL susceptibility was evaluated by LD score regression. To formally test variation in blood cell traits as potential causal pathways in ALL development, we conducted Mendelian randomization (MR) analyses, which use genetic predictors of blood cell phenotypes to overcome potential confounding and reverse causation in directly measured blood counts. Genetic instruments for MR were developed using a two-stage GWAS of 6 cell types (lymphocytes, monocytes, neutrophils, eosinophils, basophils, platelets), and their ratios (lymphocyte/monocyte - LMR; neutrophil/monocyte - NLR; platelet/lymphocyte - PLR) in the UKB. Next we applied multi-trait analysis of GWAS (MTAG) to improve power for identifying trait-specific loci by exploiting the correlated nature of blood cell traits. Causal odds ratios (OR) for ALL were estimated per 1 standard deviation increase in normalized cell counts (109cells/L) or 1-unit increase in cell type ratios. Results: Using genome-wide SNP data, we found that ALL has a heritability of hg=0.235 (95% confidence intervals, CI:0.203-0.268) in European ancestry individuals. In LD score regression, ALL susceptibility was correlated at the genetic level with overall blood cell counts (rg=0.070, P=0.003), lymphocyte counts (rg=0.088, P=0.004), LMR (rg=0.065, P=0.012), and PLR (rg= -0.072, P=0.001). Genetic instruments for MR were selected from independent (LD r2<0.05) variants with P<5×10-8 in the discovery blood cell trait GWAS/MTAG (N=234,778) and P<0.05 in the replication analysis (N=100,554). The resulting genetic predictors explained between 4.0% (basophils, NSNP=144) and 23.9% (platelets, NSNP=661) of trait variation. Our findings lend support to a modest but significant causal effect of variation in lymphocyte counts (OR=1.16, 95% CI:1.01-1.33), LMR (OR=1.23, 95% CI:1.07-1.41), NLR (OR=0.67, 95% CI:0.54-0.83), and PLR (OR=0.80, 95% CI:0.70-0.92) on ALL risk. There was no evidence of directional pleiotropy based on the MR Egger intercept test (P>0.05). However, significant heterogeneity among SNP-specific causal effects (Cochran's Q P<0.05) indicated potential for confounding due to balanced pleiotropy. In sensitivity analyses using MR-PRESSO framework, which corrects for distortion in causal effects due to pleiotropy, the associations with ALL risk became attenuated for lymphocytes (OR=1.14, 95% CI:0.98-1.32), but persisted for LMR (OR=1.18, 95% CI:1.01-1.38), NLR (OR=0.76, 95% CI:0.60-0.97), and PLR (OR=0.82, 95% CI:0.70-0.95). Next, we searched for individual variants that may underlie the effects on ALL risk using heterogeneity-based clustering of genetic instruments. This analysis confirmed that regulation of blood cell traits partially mediates the effects of known ALL risk variants: rs4948492, rs4245597 (ARID5B), rs2239630 (CEBPE), and rs78697948 (IKZF1). We also identified putative novel ALL risk loci at chromosome 2q22 (OR=1.28, P=2.5×10-6), chr6q23 (OR=1.21, P=9.3×10-6), and chr13q12 (OR=1.79, P=3.2×10-5), though further analyses are required to confirm these associations and identify likely causal variants and genes at these loci. Conclusions: Our findings suggest that dysregulation of blood cell profiles characterized by a genetic predisposition to increased lymphocyte counts, particularly in relation to neutrophils, monocytes, and platelets, confers a modest but significant increase in ALL risk. Additional research is required to determine whether a genetic propensity to higher lymphocyte levels is associated with ALL subtypes or clinical outcomes in ALL patients. Disclosures Ma: Celgene/BMS: Research Funding; BMS: Consultancy.

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Insulin-like Growth Factor-1, Bone Mineral Density, and Fracture: A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa963 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Zi-Hao Wan ◽

Shi-Le Cheng ◽

Karl Michaëlsson ◽

Susanna C Larsson

Keyword(s):

Bone Mineral Density ◽

Growth Factor ◽

Bone Mineral ◽

Odds Ratio ◽

Mendelian Randomization ◽

European Ancestry ◽

Insulin Like Growth Factor ◽

Mineral Density ◽

Genome Wide ◽

Genetic Instruments

Abstract Context The associations of circulating insulin-like growth factor-1 (IGF-1) levels with bone mineral density and fracture risk are inconclusive in observational studies. Objective We conducted a mendelian randomization study to assess the associations of serum IGF-1 levels with estimated bone mineral density (eBMD) and fracture. Methods Genetic instruments for IGF-1 were selected at the genome-wide significance level (P < 5 × 10–8) from a genome-wide association study including 358 072 individuals of European ancestry. Summary-level data for eBMD (426 824 individuals) and fracture (53 184 fracture cases and 373 611 noncases) were obtained from the UK Biobank study. Univariable and multivariable mendelian randomization analyses methods were used to estimate the associations of IGF-1 with eBMD and fracture. The main outcome measure included the change of eBMD and odds ratio of fracture per genetically predicted 1-SD increase of serum IGF-1 levels. Results For 1-SD increase in IGF-1, the change of eBMD levels was 0.04 g/cm2 (95% CI, 0.01-0.07; P = .011) and the odds ratio of fracture was 0.94 (95% CI, 0.91-0.98; P = .003). The associations persisted with similar magnitude after adjustment for height. The association was consistent for fracture but not for eBMD after excluding genetic instruments that might directly influence these outcomes. The association between IGF-1 and fracture was somewhat attenuated after adjustment for eBMD (odds ratio 0.96; 95% CI, 0.92-0.99; P = .012). Conclusion The present study supports a role for IGF-1 in preventing fracture, possibly and partly mediated by greater bone mineral density.

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Association Between Covid-19 and Heart Failure: Evidence From a Two-sample Mendelian Randomization Study

10.21203/rs.3.rs-277791/v1 ◽

2021 ◽

Author(s):

Huachen Wang ◽

Zheng Guo ◽

Yulu Zheng ◽

Bing Chen

Keyword(s):

Heart Failure ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Meta Analysis ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Reverse Causality ◽

Genome Wide ◽

Weighted Median

Abstract Background: Current research observing inconsistent associations of Corona Virus Disease 2019 (COVID-19) with heart failure (HF) are prone to bias based on reverse causality and residual confounding factors. Our aim was to apply a two-sample Mendelian randomization method to investigate whether COVID-19 has a causal effect on HF. Methods: Twenty-nine single nucleotide polymorphisms (SNPs) were proposed as candidate instrumental variables (IVs). A total of 3,523 patients with COVID-19 and 36,634 control participants were included in the genome-wide meta-analysis. We analyzed the largest genome-wide association studies (GWAS) meta-analysis of heart failure in individuals of European ancestry consisting of 47,309 patients with HF and 930,014 controls. The inverse variance weighted (IVW), the Mendelian randomization-Egger (MR-Egger) regression, the simple mode (SM), weighted median, and weighted mode were utilized for the MR analysis to test the stability and a causal effect. Results: The IVW, MR-Egger regression, SM, weighted median and weighted mode demonstrated there was no association between the genetically predicted COVID-19 infection and HF risk (OR, 1.004; 95%CI, 0.994-1.014; P=0.467; OR, 1.008; 95%CI, 0.996-1.019; P=0.218; OR, 0.968; 95%CI, 0.924-1.015; P=0.186; OR, 1.001; 95%CI, 0.988-1.014; P=0.881; OR, 1.001; 95%CI, 0.989-1.014; P=0.836; respectively). Conclusion: This two-sample Mendelian randomization analysis provided no evidence to sustain the causality of COVID-19 on HF.

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The Impact of Homocysteine on the Risk of Hormone-Related Cancers: A Mendelian Randomization Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.645371 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qian He ◽

Ze Yang ◽

Yandi Sun ◽

Zihao Qu ◽

Xueyao Jia ◽

...

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphisms ◽

Mendelian Randomization ◽

Meta Analysis ◽

Plasma Homocysteine ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

The Impact

Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.

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A causal relationship between cigarette smoking and type 2 diabetes mellitus: A Mendelian randomization study

Scientific Reports ◽

10.1038/s41598-019-56014-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Shuai Yuan ◽

Susanna C. Larsson

Keyword(s):

Type 2 Diabetes ◽

Cigarette Smoking ◽

Causal Relationship ◽

Mendelian Randomization ◽

Meta Analysis ◽

Smoking Initiation ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide

AbstractThe causality between smoking and type 2 diabetes is unclear. We conducted a two-sample Mendelian randomization study to explore the causal relationship between smoking initiation and type 2 diabetes. Summary-level data for type 2 diabetes were obtained from a meta-analysis of 32 genome-wide association studies (DIAbetes Genetics Replication And Meta-analysis consortium), which included 898 130 individuals of European ancestry. Totally, 377 single-nucleotide polymorphisms associated with smoking initiation at genome wide significance threshold (p < 5 × 10−8) were identified from the hitherto largest genome-wide association study on smoking. The inverse-variance weighted, weighted median, MR-Egger regression, and MR-PRESSO approaches were used to analyze the data. Genetically predicted smoking initiation was associated with type 2 diabetes with an odds ratio of 1.28 (95% confidence interval, 1.20, 1.37; p = 2.35 × 10−12). Results were consistent across sensitivity analyses and there was no evidence of horizontal pleiotropy. This study provides genetic evidence supporting a causal association between the smoking initiation and type 2 diabetes. Reducing cigarette smoking initiation can now be even more strongly recommended for type 2 diabetes prevention.

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The genetic architecture of sporadic and multiple consecutive miscarriage

Nature Communications ◽

10.1038/s41467-020-19742-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Triin Laisk ◽

Ana Luiza G. Soares ◽

Teresa Ferreira ◽

Jodie N. Painter ◽

Jenny C. Censin ◽

...

Keyword(s):

Odds Ratio ◽

Genetic Architecture ◽

Large Scale ◽

Mendelian Randomization ◽

Meta Analysis ◽

Complex Trait ◽

Pregnancy Complication ◽

European Ancestry ◽

Association Analyses ◽

Genome Wide

AbstractMiscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

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Causal Association of Coffee Consumption and Total, Knee, Hip and Self-Reported Osteoarthritis: A Mendelian Randomization Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.768529 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yangchang Zhang ◽

Jun Fan ◽

Li Chen ◽

Yang Xiong ◽

Tingting Wu ◽

...

Keyword(s):

Mendelian Randomization ◽

Coffee Consumption ◽

Causal Effects ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Causal Association ◽

Knee Oa ◽

Total Knee ◽

Genetic Instruments

BackgroundThe causal association between coffee consumption and the risk of OA is limited. This study was conducted to identify the potential causal effects of coffee consumption on total, knee, hip, and self-reported OA.MethodsGenome-wide association studies (GWAS) of OA were derived from the UK Biobank, comprising 50,508 participants of European ancestry (10,083 with cases and 40,425 controls), and genetic data for specific diagnosed knee OA (4462 cases and 17,885 controls), hip OA (12,625 cases and 50,898 controls), and self-reported OA (12,658 cases and 50,898 controls). Primary and secondary genetic instruments (11 SNPs and 8 SNPs) were selected as instrumental variants from GWAS among 375,833 and 91,462 participants. Two-sample Mendelian randomization (MR) analyses were performed to test the effects of the selected single nucleotide polymorphisms (SNPs) and the OA risk. The causal effects were primarily estimated using weighted median and inverse-variance weighted method with several sensitivity analyses.ResultsThe MR analyses suggested that genetically predicted 1% increase of coffee consumption was associated with an increased risk of overall OA (OR:1.009, 95% CI:1.003-1.016), knee OA (OR:1.023, 95% CI:1.009-1.038), self-reported OA (OR:1.007, 95% CI:1.003-1.011), but not hip OA (OR: 1.012, 95%CI:0.999-1.024) using primary genetic instruments. Similar results were found when using secondary genetic instruments that genetically predicted coffee consumption (cups/day). Additionally, the sensitivity analyses for leave-one-out methods supported a robust association between exposure traits and OA.ConclusionOur findings indicate that genetically predicted coffee consumption exerts a causal effect on total, knee, and self-reported OA risk, but not at the hip. Further research is required to unravel the role of coffee consumption in OA prevention.

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