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

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Pre-pregnancy body mass index and time to pregnancy among couples pregnant within a year: A China cohort study

PLoS ONE ◽

10.1371/journal.pone.0231751 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0231751

Author(s):

Yuhang Fang ◽

Jun Liu ◽

Yanyan Mao ◽

Yang He ◽

Min Li ◽

...

Keyword(s):

Body Mass Index ◽

Cohort Study ◽

Body Mass ◽

Time To Pregnancy

Download Full-text

Trajectory of blood pressure, body mass index, cholesterol and incident dementia: systematic review

The British Journal of Psychiatry ◽

10.1192/bjp.2019.156 ◽

2019 ◽

Vol 216 (1) ◽

pp. 16-28 ◽

Cited By ~ 7

Author(s):

Ruth Peters ◽

Jean Peters ◽

Andrew Booth ◽

Kaarin J. Anstey

Keyword(s):

Systematic Review ◽

Blood Pressure ◽

Body Mass Index ◽

Risk Factor ◽

Cognitive Decline ◽

Body Mass ◽

Current Evidence ◽

Ageing Population ◽

Published Evidence ◽

Current Evidence Base

BackgroundThe global ageing population and the long prodromal period for the development of cognitive decline and dementia brings a need to understand the antecedents of both successful and impaired cognitive ageing. It is increasingly apparent that the trajectory of risk-factor change, as well as the level of the risk factor, may be associated with an increased or decreased risk of cognitive decline or dementia.AimsOur aim was to summarise the published evidence and to generate hypotheses related to risk-factor trajectories and risk of incident cognitive decline or dementia.MethodWe collated data from longitudinal observational studies relating to trajectory of blood pressure, obesity and cholesterol and later cognitive decline or dementia using standard systematic review methodology. The databases MEDLINE, Embase and PsycINFO were searched from inception to 26 April 2018.ResultsThirteen articles were retained for inclusion. Analytical methods varied. Our summary of the current evidence base suggests that first body mass index and then blood pressure rises and then falls more steeply in those who go on to develop dementia. The evidence for cholesterol was less consistent.ConclusionBased on our review we present the hypothesis that weight falls around 10 years and blood pressure around 5 years before diagnosis. Confirmatory work is required. However, characterisation of risk according to combinations and patterns of risk factors may ultimately be integrated into the assessments used to identify those at risk of receiving a diagnosis of cognitive decline or dementia in late life.

Download Full-text

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.

Download Full-text

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

International Journal of Epidemiology ◽

10.1093/ije/dyz240 ◽

2019 ◽

Vol 49 (4) ◽

pp. 1173-1184 ◽

Cited By ~ 4

Author(s):

Laura D Howe ◽

Roshni Kanayalal ◽

Sean Harrison ◽

Robin N Beaumont ◽

Alisha R Davies ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Specific Effect ◽

Economic Outcomes ◽

European Ancestry ◽

Uk Biobank ◽

Non Linear ◽

Low Bmi ◽

Economic Position

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.

Download Full-text

Relationship between body mass index and depression in women: A 7-year prospective cohort study. The APNA study

European Psychiatry ◽

10.1016/j.eurpsy.2015.11.003 ◽

2016 ◽

Vol 32 ◽

pp. 55-60 ◽

Cited By ~ 20

Author(s):

E. Martin-Rodriguez ◽

F. Guillen-Grima ◽

E. Aubá ◽

A. Martí ◽

A. Brugos-Larumbe

Keyword(s):

Body Mass Index ◽

Cohort Study ◽

Body Mass ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Adult Women ◽

Obese Women ◽

Weight Category ◽

Kaplan Meier

AbstractBackgroundThe association between body mass index (BMI) and depression is complex and controversial. The present study examined the relationship between BMI and new-onset depression during 7 years of follow-up in 20,212 adult women attending Primary Health Care Centres in Navarra, Spain.MethodsThe Atención Primaria de Navarra (APNA) study is a dynamic prospective cohort study. A total of 20,212 women aged 18–99 years (mean age: 50.7 ± 18.5 years) without depression at baseline were selected from 2004 to 2011. We estimated the incidence of depression. We used the Kaplan-Meier analysis to predict the survival curve. The risk of depression onset according to different measures of BMI at baseline was assessed using Cox regression analyses.ResultsDuring the 7 years of follow-up, depression appeared in 8.9% (95% CI 8.5–9.3). The highest rates of depression incidence at follow-up occurred in underweight and obese women (9.8% [95% CI 7.3–12.9] and 10.3% [95% CI 9.5–11.1] respectively). The distribution of depression incidence by weight category was U-shaped. The risk of depression increased over time with an observed Kaplan-Meier estimation of 6.67. After adjusting for age, underweight and obese women at baseline have increased risk of depression onset during the follow-up period compared with normal weight women (HR = 1.48, 95% CI = 1.09–2.00 and HR = 1.14, 95% CI = 1.01–1.29 respectively).ConclusionsIn this 7-year prospective study in the APNA women population, depression emerged in 8.9%. Being underweight or obese (not overweight) at baseline is significantly associated with future onset of depression.

Download Full-text

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003413 ◽

2020 ◽

Vol 17 (11) ◽

pp. e1003413

Author(s):

Tormod Rogne ◽

Erik Solligård ◽

Stephen Burgess ◽

Ben M. Brumpton ◽

Julie Paulsen ◽

...

Keyword(s):

Body Mass Index ◽

General Population ◽

Bloodstream Infection ◽

Body Mass ◽

Mendelian Randomization ◽

Obesity Paradox ◽

Hazard Ratio ◽

European Ancestry ◽

Health Study ◽

Incidence And Mortality

Background In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. Methods and findings We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. Conclusions Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the “obesity paradox,” where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis.

Download Full-text