Effects of body mass index on relationship status, social contact and socio-economic position: Mendelian randomization and within-sibling study in UK Biobank

Abstract Background We assessed whether body mass index (BMI) affects social and socio-economic outcomes. Methods We used Mendelian randomization (MR), non-linear MR and non-genetic and MR within-sibling analyses, to estimate relationships of BMI with six socio-economic and four social outcomes in 378 244 people of European ancestry in UK Biobank. Results In MR of minimally related individuals, higher BMI was related to higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. Non-linear MR suggested both low (bottom decile, <22 kg/m2) and high (top seven deciles, >24.6 kg/m2) BMI, increased deprivation and reduced income. Non-genetic within-sibling analysis supported an effect of BMI on socio-economic position (SEP); precision in within-sibling MR was too low to draw inference about effects of BMI on SEP. There was some evidence of pleiotropy, with MR Egger suggesting limited effects of BMI on deprivation, although precision of these estimates is also low. Non-linear MR suggested that low BMI (bottom three deciles, <23.5 kg/m2) reduces the odds of cohabiting with a partner or spouse in men, whereas high BMI (top two deciles, >30.7 kg/m2) reduces the odds of cohabitation in women. Both non-genetic and MR within-sibling analyses supported this sex-specific effect of BMI on cohabitation. In men only, higher BMI was related to lower participation in leisure and social activities. There was little evidence that BMI affects visits from friends and family or having someone to confide in. Conclusions BMI may affect social and socio-economic outcomes, with both high and low BMI being detrimental for SEP, although larger within-family MR studies may help to test the robustness of MR results in unrelated individuals. Triangulation of evidence across MR and within-family analyses supports evidence of a sex-specific effect of BMI on cohabitation.

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Effects of body mass index on relationship status, social contact, and socioeconomic position: Mendelian Randomization study in UK Biobank

10.1101/524488 ◽

2019 ◽

Cited By ~ 2

Author(s):

Laura D Howe ◽

Roshni Kanayalal ◽

Robin N Beaumont ◽

Alisha R Davies ◽

Timothy M Frayling ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Relationship Status ◽

Social Activities ◽

Uk Biobank ◽

Non Linear ◽

Low Bmi ◽

Degree Level ◽

High Bmi

AbstractObjectiveTo assess whether body mass index (BMI) has a causal effect on social and socioeconomic factors, including whether both high and low BMI can be detrimental.DesignMendelian Randomization, using genetic variants for BMI to obtain unconfounded estimates, and non-linear Mendelian Randomization.SettingUK Biobank.Participants378,244 men and women of European ancestry, mean age 57 (SD 8 years).Main outcome measuresTownsend deprivation index, income, age completed full time education, degree level education, job class, employment status, cohabiting relationship status, participation in leisure and social activities, visits from friends and family, and having someone to confide in.ResultsHigher BMI was causally associated with higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. For example, a 1 SD higher genetically-determined BMI (4.8kg/m2 in UK Biobank) was associated with £1,660 less income per annum [95%CI: £950, £2,380]. Non-linear Mendelian Randomization provided evidence that both low BMI (bottom decile, <22kg/m2) and high BMI (top seven deciles, >24.6kg/m2) can increase deprivation and reduce income. In men only, higher BMI was related to lower participation in leisure and social activities. There was no evidence of causal effects of BMI on visits from friends and family or in having someone to confide in. Non-linear Mendelian Randomization analysis showed that low BMI (bottom three deciles, <23.5kg/m2) reduces the odds of cohabiting with a partner or spouse for men, whereas high BMI (top two deciles, >30.7kg/m2) reduces the odds of cohabitation with a partner or spouse for women.ConclusionsBMI affects social and socioeconomic outcomes, with both high and low BMI being detrimental for some measures of SEP. This suggests that in addition to health benefits, maintaining healthy ranges of BMI across the population could have benefits both for individuals and society.

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Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

10.1101/2021.06.21.21259264 ◽

2021 ◽

Author(s):

Alvaro Hernaez ◽

Tormod Rogne ◽

Karoline H. Skara ◽

Siri E. Haberg ◽

Christian M. Page ◽

...

Keyword(s):

Body Mass Index ◽

Cohort Study ◽

Body Mass ◽

Mendelian Randomization ◽

European Ancestry ◽

Current Evidence ◽

Obese Women ◽

Time To Pregnancy ◽

Current Evidence Base ◽

Multivariable Regression

Background. Higher body mass index (BMI) is associated with subfertility in women and men. This relationship is further substantiated by a few small randomized-controlled trials of weight reduction and success of assisted reproduction. The aim of the current study was to expand the current evidence-base by investigating the association between BMI and subfertility in men and women using multivariable regression and Mendelian randomization. Methods and findings. We studied 34,157 women (average age 30, average BMI 23.1 kg/m2) and 31,496 men (average age 33, average BMI 25.4 kg/m2) who were genotyped and are participating in the Norwegian Mother, Father and Child Cohort Study. Self-reported information was available on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear Mendelian randomization validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 15% greater odds of subfertility (95% confidence interval 4% to 28%) in obese women (>=30.0 kg/m2) and 14% lower odds of subfertility (-25% to -3%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 23% greater odds of subfertility (6% to 43%) among obese men and 36% decreased odds (-62% to 7%) among men BMI <20.0 kg/m2. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. The main limitations of our study were that we did not know whether the subfertility was driven by the woman, man, or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2. Conclusions. We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization analysis, further supporting a potential causal role of BMI on subfertility.

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Body mass index and mortality in UK Biobank: revised estimates using Mendelian randomization

10.1101/281436 ◽

2018 ◽

Cited By ~ 2

Author(s):

Kaitlin H Wade ◽

David Carslake ◽

Naveed Sattar ◽

George Davey Smith ◽

Nicholas J Timpson

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Causal Effect ◽

Genotypic Variation ◽

Lung Cancer Mortality ◽

Causal Role ◽

Uk Biobank ◽

All Cause Mortality

AbstractObjectiveObtain estimates of the causal relationship between different levels of body mass index (BMI) and mortality.MethodsMendelian randomization (MR) was conducted using genotypic variation reliably associated with BMI to test the causal effect of increasing BMI on all-cause and cause-specific mortality in participants of White British ancestry in UK Biobank.ResultsMR analyses supported existing evidence for a causal association between higher levels of BMI and greater risk of all-cause mortality (hazard ratio (HR) per 1kg/m2: 1.02; 95% CI: 0.97,1.06) and mortality from cardiovascular diseases (HR: 1.12; 95% CI: 1.02, 1.23), specifically coronary heart disease (HR: 1.19; 95% CI: 1.05, 1.35) and those other than stroke/aortic aneurysm (HR: 1.13; 95% CI: 0.93, 1.38), stomach cancer (HR: 1.30; 95% CI: 0.91, 1.86) and oesophageal cancer (HR: 1.08; 95% CI: 0.84, 1.38), and with decreased risk of lung cancer mortality (HR: 0.97; 95% CI: 0.84, 1.11). Sex-stratified analyses supported a causal role of higher BMI in increasing the risk of mortality from bladder cancer in males and other causes in females, but in decreasing the risk of respiratory disease mortality in males. The characteristic J-shaped observational association between BMI and mortality was visible with MR analyses but with a smaller value of BMI at which mortality risk was lowest and apparently flatter over a larger range of BMI.ConclusionResults support a causal role of higher BMI in increasing the risk of all-cause mortality and mortality from other causes. However, studies with greater numbers of deaths are needed to confirm the current findings.

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Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1002982 ◽

2019 ◽

Vol 16 (12) ◽

pp. e1002982 ◽

Cited By ~ 6

Author(s):

Michael Wainberg ◽

Anubha Mahajan ◽

Anshul Kundaje ◽

Mark I. McCarthy ◽

Erik Ingelsson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Uk Biobank ◽

The Uk

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Maternal Hypertension Increases Risk of Preeclampsia and Low Fetal Birthweight: Genetic Evidence From a Mendelian Randomization Study

Hypertension ◽

10.1161/hypertensionaha.121.18617 ◽

2022 ◽

Author(s):

Maddalena Ardissino ◽

Eric A.W. Slob ◽

Ophelia Millar ◽

Rohin K. Reddy ◽

Laura Lazzari ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Body Mass Index ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Body Mass ◽

Mendelian Randomization ◽

European Ancestry ◽

Increased Risk

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45–2.49]; P =3.23×10 −6 ) and reduced birthweight (OR=0.83 [95% CI=0.79–0.86]; P =3.96×10 −18 ), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44–1.94]; P =7.45×10 −12 ; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04–1.19]; P =1.19×10 −3 ), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

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Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis

International Journal of Obesity ◽

10.1038/s41366-021-00807-4 ◽

2021 ◽

Author(s):

Dipender Gill ◽

Verena Zuber ◽

Jesse Dawson ◽

Jonathan Pearson-Stuttard ◽

Alice R. Carter ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

European Ancestry ◽

Standard Deviation Increase ◽

Waist To Hip Ratio ◽

Artery Disease

Abstract Background Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood. Methods Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke. Results The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome. Conclusions Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.

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Searching for the causal effects of body mass index in over 300 000 participants in UK Biobank, using Mendelian randomization

PLoS Genetics ◽

10.1371/journal.pgen.1007951 ◽

2019 ◽

Vol 15 (2) ◽

pp. e1007951 ◽

Cited By ~ 23

Author(s):

Louise A. C. Millard ◽

Neil M. Davies ◽

Kate Tilling ◽

Tom R. Gaunt ◽

George Davey Smith

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Causal Effects ◽

Uk Biobank

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Causal linkage between adult height and kidney function: An integrated population-scale observational analysis and Mendelian randomization study

PLoS ONE ◽

10.1371/journal.pone.0254649 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254649

Author(s):

Sehoon Park ◽

Soojin Lee ◽

Yaerim Kim ◽

Yeonhee Lee ◽

Min Woo Kang ◽

...

Keyword(s):

Body Mass Index ◽

Kidney Function ◽

Body Mass ◽

Standard Error ◽

Adult Height ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Uk Biobank ◽

Cross Sectional ◽

Observational Analysis

As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFRcreatinine) or cystatin C (eGFRcystatinC) was investigated in 467,182 individuals aged 40–69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFRcreatinine and CKDcreatinine in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFRcystatinC and CKDcystatinC in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFRcreatinine (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFRcystatinC (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFRcreatinine (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKDcreatinine (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFRcystatinC (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKDcystatinC (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index.

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Evidence of a common causal relationship between body mass index and inflammatory skin disease: a Mendelian Randomization study

10.1101/265629 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ashley Budu-Aggrey ◽

Ben Brumpton ◽

Jess Tyrrell ◽

Sarah Watkins ◽

Ellen H Modalsli ◽

...

Keyword(s):

Body Mass Index ◽

Causal Relationship ◽

Body Mass ◽

Skin Disease ◽

Skin Diseases ◽

Mendelian Randomization ◽

Uk Biobank ◽

Inflammatory Skin Disease ◽

Level Data ◽

Inflammatory Skin

ABSTRACTObjectivePsoriasis and eczema are common inflammatory skin diseases that have been reported to be associated with obesity. However, causality has not yet been established. We aimed to investigate the possible causal relationship between body mass index (BMI) and psoriasis or eczema.MethodsFollowing a review of published epidemiological evidence of the association between obesity and either psoriasis or eczema, Mendelian Randomization (MR) was used to test for a causal relationship between BMI and these inflammatory skin conditions. We used a genetic instrument comprising 97 single nucleotide polymorphisms (SNPs) associated with BMI. One-sample MR was conducted using individual-level data (401,508 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (731,021 individuals) from published BMI, psoriasis and eczema GWAS. The one-sample and two-sample MR estimates were meta-analysed using a fixed effect model. To explore the reverse causal direction, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis and eczema were used to test if inflammatory skin disease has a causal effect on BMI.ResultsPublished observational data show an association of greater BMI with both psoriasis and eczema case status. The observational associations were confirmed in UK Biobank and HUNT datasets. MR analyses provide evidence that higher BMI causally increases the odds of psoriasis (by 53% per 5 units higher BMI; OR= 1.09 (1.06 to 1.12) per 1 kg/m2; P=4.67×10-9) and eczema (by 8% per 5 units higher BMI; OR=1.02 (1.00 to 1.03) per 1 kg/m2; P=0.09). When investigating causality in the opposite direction, MR estimates provide little evidence for an effect of either psoriasis or eczema influencing BMI.ConclusionOur study, using genetic variants as instrumental variables for BMI, shows that higher BMI leads to a higher risk of inflammatory skin disease. The causal relationship was stronger for psoriasis than eczema. Therapies and life-style interventions aimed at controlling BMI or targeting the mechanisms linking obesity with skin inflammation may offer an opportunity for the prevention or treatment of these common skin diseases.

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Elucidation of causal direction between asthma and obesity: a bi-directional Mendelian randomization study

International Journal of Epidemiology ◽

10.1093/ije/dyz070 ◽

2019 ◽

Vol 48 (3) ◽

pp. 899-907 ◽

Cited By ~ 11

Author(s):

Shujing Xu ◽

Frank D Gilliland ◽

David V Conti

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Causal Effect ◽

European Ancestry ◽

Summary Statistics ◽

Adult Body Mass ◽

Causal Direction ◽

Genome Wide ◽

Adult Body

Abstract Background Observational associations between asthma and obesity are well established, but inferring causality is challenging. We leveraged publicly available summary statistics to ascertain the causal direction between asthma and obesity via Mendelian randomization in European-ancestry adults. Methods We performed two-sample bi-directional Mendelian randomization analysis using publicly available genome-wide association studies summary statistics. Single nucleotide polymorphisms associated with asthma and body mass index at genome-wide significance were combined using a fixed effect meta-analysis in each direction. An extensive sensitivity analysis was considered. Results There was evidence in support of increasing causal effect of body mass index on risk of asthma (odds ratio 1.18 per unit increase, 95% confidence interval (CI) (1.11, 1.25), P = 2 × 10−8. No significant causal effect of asthma on adult body mass index was observed [estimate −0.004, 95% CI (−0.018, 0.009), P = 0.553]. Conclusions Our results confirmed that in European-ancestry populations, adult body mass index is likely to be causally linked to the risk of asthma; yet the effect of asthma on body mass index is small, if present at all.

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