Obesity‐Related Traits and the Development of Rheumatoid Arthritis: Evidence From Genetic Data

Tang, Bowen; Shi, Huwenbo; Alfredsson, Lars; Klareskog, Lars; Padyukov, Leonid; Jiang, Xia

doi:10.1002/art.41517

Cited by 31 publications

(24 citation statements)

References 38 publications

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“…The number of MR studies based on independent study samples for each disease category was two for diabetes mellitus [ 7 , 8 ], 13 for circulatory system diseases [ 9 – 21 ], three for respiratory diseases [ 8 , 22 , 23 ], six for digestive system diseases [ 24 – 29 ], five for musculoskeletal system diseases [ 30 – 34 ] plus FinnGen consortium (for osteoporosis), five for nervous system diseases [ 35 – 39 ], and 14 for neoplasms [ 40 – 53 ]. Among the selected studies, six studies included East-Asian (Chinese [ 11 , 25 , 42 ] and Japanese [ 48 , 50 ]) or Chilean [ 53 ] individuals, whereas the remaining studies included individuals of European ancestry or mixed (trans-ancestry) populations.…”

Section: Resultsmentioning

confidence: 99%

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Larsson

Burgess

2021

BMC Med

142

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Background Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases. Methods PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals). Results In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren’s disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s disease. Conclusions The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal.

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Section: Resultsmentioning

confidence: 99%

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Larsson

Burgess

2021

BMC Med

142

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“…A significant result was also observed for WHR and PCOS ( r g =0.32, P =1.34×10 −10 ). Given the complex interplay between BMI and WHR [ 29 ], we continued to investigate WHR ad jBMI, a residual component of WHR in which the effect of BMI was removed. Perhaps not surprisingly, when the effect of BMI was removed from WHR (WHR adj BMI), the prior positive genetic correlation between PCOS and WHR was attenuated to null (WHR adj BMI: r g =0.09, P =0.04).…”

Section: Resultsmentioning

confidence: 99%

Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis

Liu

Zhu

Kraft

et al. 2022

BMC Med

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Background The comorbidity between polycystic ovary syndrome (PCOS) and obesity has long been observed in clinical settings, but their shared genetic basis remains unclear. Methods Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on body mass index (adult BMI, Nfemale=434,794; childhood BMI, N=39,620), waist-to-hip ratio (WHR, Nfemale=381,152), WHR adjusted for BMI (WHRadjBMI, Nfemale=379,501), and PCOS (Ncase=10,074, Ncontrol=103,164), we performed a large-scale genome-wide cross-trait analysis to quantify overall and local genetic correlation, to identify shared loci, and to infer causal relationship. Results We found positive genetic correlations between PCOS and adult BMI (rg=0.47, P=2.19×10−16), childhood BMI (rg=0.31, P=6.72×10−5), and WHR (rg=0.32, P=1.34×10−10), all withstanding Bonferroni correction. A suggestive significant genetic correlation was found between PCOS and WHRadjBMI (rg=0.09, P=0.04). Partitioning the whole genome into 1703 nearly independent regions, we observed a significant local genetic correlation for adult BMI and PCOS at chromosome 18: 57630483–59020751. We identified 16 shared loci underlying PCOS and obesity-related traits via cross-trait meta-analysis including 9 loci shared between BMI and PCOS (adult BMI and PCOS: 5 loci; childhood BMI and PCOS: 4 loci), 6 loci shared between WHR and PCOS, and 5 loci shared between WHRadjBMI and PCOS. Mendelian randomization (MR) supported the causal roles of both adult BMI (OR=2.92, 95% CI=2.33–3.67) and childhood BMI (OR=2.76, 95% CI=2.09–3.66) in PCOS, but not WHR (OR=1.19, 95% CI=0.93–1.52) or WHRadjBMI (OR=1.03, 95% CI=0.87–1.22). Genetic predisposition to PCOS did not seem to influence the risk of obesity-related traits. Conclusions Our cross-trait analysis suggests a shared genetic basis underlying obesity and PCOS and provides novel insights into the biological mechanisms underlying these complex traits. Our work informs public health intervention by confirming the important role of weight management in PCOS prevention.

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“…An MR study demonstrated that a one-year delay in age at menarche reduced adult BMI by 0.38kg/m 2 (95%CI 0.25-0.51kg/m 2 ). [25] Global adiposity is a robust causal risk factor for RA as demonstrated by our recently published MR. [26] It is likely that traditional epidemiological investigations did not adequately control for the confounding effects from obesity. The protective effect of education on RA has been reported by observational studies.…”

Section: Discussionmentioning

confidence: 99%

Age at menarche, age at natural menopause and risk of rheumatoid arthritis – a Mendelian randomization study

Zhu

Niu

Alfredsson

et al. 2021

Preprint

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Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM) and age at first birth (AFB) with the risk of RA.Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N=329,345), ANM (N=69,360), AFB (N=251,151) and RA (Ncase=14,361, Ncontrol=43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted-median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM=1.06 [0.98-1.15]; ORper-SD increment in ANM=1.05 [0.98-1.11], OR per-SD increment in AFB=0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM=1.06 [0.97-1.15], ORper-SD increment in ANM=1.05 [0.98-1.13], ORper-SD increment in AFB=0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM=1.03 [0.94-1.12], ORper-SD increment in ANM=1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

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Obesity‐Related Traits and the Development of Rheumatoid Arthritis: Evidence From Genetic Data

Cited by 31 publications

References 38 publications

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis

Age at menarche, age at natural menopause and risk of rheumatoid arthritis – a Mendelian randomization study

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