Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Jiayao Fan ◽  
Jiahao Zhu ◽  
Lingling Sun ◽  
Yasong Li ◽  
Tianle Wang ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Knee Oa ◽  
Genome Wide ◽  
A Genome ◽  
Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

scholarly journals Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

2018 ◽  
Vol 28 (1) ◽  
pp. 166-174 ◽  
Author(s):  
Sara L Pulit ◽  
Charli Stoneman ◽  
Andrew P Morris ◽  
Andrew R Wood ◽  
Craig A Glastonbury ◽  
...  
Keyword(s):  
Body Fat ◽  
Association Studies ◽  
Meta Analysis ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

scholarly journals A genome-wide association study on meat consumption in a Japanese population: the Japan Multi-Institutional Collaborative Cohort study

2021 ◽  
Vol 10 ◽  
Author(s):  
Yasuyuki Nakamura ◽  
Akira Narita ◽  
Yoichi Sutoh ◽  
Nahomi Imaeda ◽  
Chiho Goto ◽  
...  
Keyword(s):  
Japanese Population ◽  
Genetic Factors ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Meat Consumption ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population.

scholarly journals Genome-Wide Association between the 2q33.1 Locus and Intracranial Aneurysm Susceptibility: An Updated Meta-Analysis Including 18,019 Individuals

2019 ◽  
Vol 8 (5) ◽  
pp. 692
Author(s):  
Eun Pyo Hong ◽  
Bong Jun Kim ◽  
Jin Pyeong Jeon
Keyword(s):  
Intracranial Aneurysm ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Human Tissues ◽  
Genome Wide ◽  
A Genome

Previous genome-wide association studies did not show a consistent association between the BOLL gene (rs700651, 2q33.1) and intracranial aneurysm (IA) susceptibility. We aimed to perform an updated meta-analysis for the potential IA-susceptibility locus in large-scale multi-ethnic populations. We conducted a systematic review of studies identified by an electronic search from January 1990 to March 2019. The overall estimates of the “G” allele of rs700651, indicating IA susceptibility, were calculated under the fixed- and random-effect models using the inverse-variance method. Subsequent in silico function and cis-expression quantitative trait loci (cis-eQTL) analyses were performed to evaluate biological functions and genotype-specific expressions in human tissues. We included 4513 IA patients and 13,506 controls from five studies with seven independent populations: three European-ancestry, three Japanese, and one Korean population. The overall result showed a genome-wide significance threshold between rs700651 and IA susceptibility after controlling for study heterogeneity (OR = 1.213, 95% CI: 1.135–1.296). Subsequent cis-eQTL analysis showed significant genome-wide expressions in three human tissues, i.e., testis (p = 8.04 × 10−15 for ANKRD44), tibial nerves (p = 3.18 × 10−10 for SF3B1), and thyroid glands (p = 4.61 × 10−9 for SF3B1). The rs700651 common variant of the 2q33.1 region may be involved in genetic mechanisms that increase the risk of IA and may play crucial roles in regulatory functions.

scholarly journals Adipokines and risk of rheumatoid arthritis: a Mendelian randomization study

2020 ◽  
Author(s):  
Jiahao Zhu ◽  
Haiyan Zheng ◽  
Yasong Li ◽  
Tianle Wang ◽  
Yaohong Zhong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Statistical Significance ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Primary Analysis ◽  
Genome Wide

Abstract Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA.Methods: We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely.Results: The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings.Conclusions: Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.

Causal relationship of serum nutritional factors with osteoarthritis: a Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Zihao Qu ◽  
Fangkun Yang ◽  
Jianqiao Hong ◽  
Wei Wang ◽  
Sihao Li ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Serum Retinol ◽  
Nutritional Factors ◽  
Knee Oa ◽  
Genome Wide

Abstract Objectives OA is the most common form of arthritis worldwide and has a major impact on the quality of life among the older population. This study aimed at determining the potential causal effects of several serum nutritional factors on OA. Methods A total of seven serum nutritional factors were identified from genome-wide association studies. Summary statistics for OA were obtained from UK Biobank (194 153 for women and 166 988 for men) and a large genome-wide association studies meta-analysis based on the European population (455 221, 393 873 and 403 124 for overall, hip and knee OA, respectively). Two-sample Mendelian randomization approach was used to estimate the causal association between the selected nutritional factors and the risk of OA. Results The Mendelian randomization analyses suggested that serum calcium levels were inversely associated with overall OA (95% CI, 0.595, 0.850), hip OA (95% CI, 0.352, 0.799) and knee OA (95% CI, 0.461, 0.901). Serum retinol levels were also inversely associated with hip OA (95% CI, 0.257, 0.778). Moreover, sex-specific associations were observed between serum calcium levels (95% CI, 0.936, 0.998), iron levels (95% CI, 1.000, 1.012), selenium levels (95% CI, 0.923, 0.999) and OA in women. Conclusion In this study, an inverse causal association between serum calcium levels and OA was established. Serum retinol levels were inversely associated with hip OA. In addition, we provide evidence for the causal effect of serum calcium, iron and selenium on the risk of OA in women.

scholarly journals Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hang-Rai Kim ◽  
Sang-Hyuk Jung ◽  
Jaeho Kim ◽  
Hyemin Jang ◽  
Sung Hoon Kang ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Prediction Models ◽  
Association Studies ◽  
Genome Wide Association ◽  
Korean Population ◽  
European Ancestry ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10−8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74–0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

scholarly journals Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry

2018 ◽  
Author(s):  
Sara L. Pulit ◽  
Charli Stoneman ◽  
Andrew P. Morris ◽  
Andrew R. Wood ◽  
Craig A. Glastonbury ◽  
...  
Keyword(s):  
Body Fat ◽  
Association Studies ◽  
Meta Analysis ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

AbstractOne in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

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

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.

scholarly journals Relationship between smoking and ALS: Mendelian randomisation interrogation of causality

2020 ◽  
Vol 91 (12) ◽  
pp. 1312-1315
Author(s):  
Sarah Opie-Martin ◽  
Robyn E Wootton ◽  
Ashley Budu-Aggrey ◽  
Aleksey Shatunov ◽  
Ashley R Jones ◽  
...  
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome

ObjectiveSmoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.MethodsTwo genome-wide association studies investigating lifetime smoking (n=463 003) and ever smoking (n=1 232 091) were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS (20 806 cases; 59 804 controls) was used as the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.ResultsThere was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.ConclusionsUsing multiple methods, large sample sizes and sensitivity analyses, we find no evidence with Mendelian randomisation techniques that smoking causes ALS. Other smoking phenotypes, such as current smoking, may be suitable for future Mendelian randomisation studies

scholarly journals International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline M. Nievergelt ◽  
Adam X. Maihofer ◽  
Torsten Klengel ◽  
Elizabeth G. Atkinson ◽  
Chia-Yen Chen ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
African Ancestry ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Sign in / Sign up

Export Citation Format

Share Document