Fig 1.
BMI, body mass index; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; GRS, genetic risk score; MAGIC, Meta-Analyses of Glucose and Insulin-related traits Consortium; MR, Mendelian randomization; NAFLD, non-alcoholic fatty liver disease; PC, principal component; SBP, systolic blood pressure; T1D, type 1 diabetes; T2D, type 2 diabetes; WHR, waist-hip ratio; WHRadjBMI, waist-hip ratio adjusted for body mass index.
Fig 2.
SNP- and weight selection flowchart with number of SNPs for each obesity trait.
SNPs were selected by combining the primary (“index”) variants associated with the obesity traits P<5×10−9 in a meta-analysis of GIANT and UK Biobank [14,22]. All SNPs were weighted by their sex-specific European estimates for the men- and women-specific analyses, and by the combined-sexes European estimates for the combined-sexes analyses, using estimates from the original genome-wide association study. BMI, body mass index; SNP, single nucleotide polymorphism; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index.
Fig 3.
Causal effects of obesity traits on disease outcomes, overall and stratified by sex.
Endpoints that showed an association with obesity GRSs were taken forward for Mendelian randomization, with estimates reported as odds ratio (95% CI) per 1-SD higher obesity trait. Filled diamonds indicate that the P-value for the obesity trait to disease endpoint surpasses our threshold for multiple testing; empty diamonds indicate that the P-value does not surpass this threshold (Bonferroni-adjusted P-value-threshold set at <0.001 (= 0.05/51) for 51 obesity trait-disease outcome combinations in the study). * denotes that the P-value for heterogeneity (from Cochran’s Q test) surpasses our threshold for multiple testing; Phet-threshold set at <0.001 (= 0.05/48) for 48 male-female comparisons in the study (fewer since breast cancer analyses were performed in women only). Green diamond, combined-sexes estimates; orange diamond, male estimates; purple diamond, female estimates; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; NAFLD, non-alcoholic fatty liver disease; SD standard deviation; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index.
Fig 4.
Overview of the sex-specific effect magnitudes and strengths of association of obesity traits on leading causes of death.
Leading causes of death defined as non-communicable diseases on the WHO top 10 lists of causes of death, globally and in high-income countries, with additional separate analyses for subclasses of stroke, diabetes, and renal disease. No obesity trait (BMI, WHR, or WHRadjBMI) genetic risk score associated with dementia, colorectal cancer, breast cancer (investigated in women only) or hemorrhagic stroke–these are not shown on the plot (for the regression results see Table F in S1 Text). (A) Total number of deaths globally, in 1,000 deaths, as estimated by the WHO for 2016 [64], stratified by sex. For diabetes, estimates for annual number of deaths are for type 1 and type 2 diabetes combined. (B) Obesity trait-disease combinations taken forward for Mendelian randomization showed with circles. Mendelian randomization associations with P-values surpassing our threshold in yellow to red fill depending on P-value (-log10 P-value), white fill indicates a P-value not surpassing our threshold. The size of the circles corresponds to the magnitude of the odds ratio estimate for the Mendelian randomization estimate. Estimates and P-values from the MR analyses of the obesity traits with the disease outcomes using the sex-specific estimates approach. BMI, body mass index; P, P-value; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index; WHO, World Health Organization.
Fig 5.
Causal effects of obesity traits on continuous risk factors, overall and stratified by sex.
The obesity-risk factor combinations brought forward for Mendelian randomization. Estimates in plasma mmol/L levels for FG, serum pmol/L levels (ln-transformed) for FI and SD-units for SBP and DBP, per 1-SD higher obesity trait. Filled diamonds indicate that the P-value for the obesity trait to risk factor endpoint surpasses our threshold for multiple testing; empty diamonds indicate that the P-value does not surpass this threshold (Bonferroni-adjusted P-value-threshold set at <0.003 (= 0.05/15) for 15 obesity trait-risk factor combinations in the study). * denotes that the P-value for heterogeneity (from Cochran’s Q test) surpasses our threshold for multiple testing; Phet-threshold set at <0.003 (= 0.05/15). Green diamond, combined-sexes estimates; orange diamond, male estimates; purple diamond, female estimates; BMI, body mass index; DBP, diastolic blood pressure; FG, fasting glucose; FI, fasting insulin; SBP, systolic blood pressure; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index.
Fig 6.
Causal effects of obesity traits on having been or being a smoker, overall and stratified by sex.
Estimates given in odds ratio (95% CI) per 1-SD higher obesity trait. Filled diamonds indicate that the P-value for the obesity trait to disease endpoint surpasses our threshold for multiple testing; empty diamonds indicate that the P-value does not surpass this threshold (Bonferroni-adjusted P-value-threshold set at <0.003 (= 0.05/15) for 15 obesity trait-risk factor combinations in the study). * denotes that the P-value for heterogeneity (from Cochran’s Q test) surpasses our threshold for multiple testing; Phet-threshold set at <0.003 (= 0.05/15). Green diamond, combined-sexes estimates; orange diamond, male estimates; purple diamond, female estimates; BMI, body mass index; SD standard deviation; WHR, waist-hip-ratio; WHRadjBMI, waist-hip-ratio adjusted for body mass index.