Challenges in undertaking nonlinear Mendelian randomization.

Mendelian randomization (MR) is a widely used method that exploits the unique properties of germline genetic variation to strengthen causal inference in relationships between exposures and outcomes. Nonlinear MR allows estimation of the shape of these relationships. In a previous paper, the authors applied linear and nonlinear MR to estimate the effect of BMI on mortality in UK Biobank, providing evidence for a J-shaped association. However, it is now clear that there are problems with widely used nonlinear MR methods, which draws attention to the likely erroneous nature of the conclusions regarding the shapes of several explored relationships. Here, the authors explore the utility and likely biases of these nonlinear MR methods with the use of a negative control design. Although there remains good evidence for a causal effect of higher BMI increasing the risk of mortality, the pattern of this association across different levels of BMI requires further characterization.

Comparison of intergenerational instrumental variable analyses of body mass index and mortality in UK Biobank.

BACKGROUND: An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants. METHODS: In Cox regression models, parental BMI was instrumented by offspring BMI using an 'offspring as instrument' (OAI) estimation and by offspring BMI-related genetic variants in a 'proxy-genotype Mendelian randomization' (PGMR) estimation. RESULTS: Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent-offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother-son) and 1.23 (95% CI: 1.16, 1.29; father-daughter). CONCLUSION: Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.

Correction: Association of physical activity intensity and bout length with mortality: An observational study of 79,503 UK Biobank participants.

[This corrects the article DOI: 10.1371/journal.pmed.1003757.].

Cardiovascular risk factors in extended family members and birthweight in offspring.

Low birthweight has been related to an increased risk of adult cardiovascular disease (CVD). Transgenerational studies have been used to investigate likely mechanisms underlying this inverse association. However, previous studies mostly examined the association of offspring birthweight with CVD risk factors among parents. In this study, we investigated the association between offspring birthweight and individual CVD risk factors, an index of CVD risk factors, and education in their parents, aunts/uncles, and aunts'/uncles' partners. Birth data (Medical Birth Registry, Norway (MBRN) (1967-2012)) was linked to CVD risk factor data (the County Study, Age 40 Program, and Cohort Norway (CONOR)) for the parents, aunts/uncles, and their partners. For body mass index (BMI), resting heart rate (RHR), systolic blood pressure (SBP), total cholesterol (TC), triglycerides (TG), and a risk factor index, the associations were examined by linear regression. For smoking and education, they were examined by logistic regression. Low birthweight was associated with an unfavorable risk factor profile in all familial relationships. For each kg increase in birthweight, the mean risk factor index decreased by -0.14 units (-0.15, -0.13) in mothers, -0.11 (-0.12, -0.10) in fathers, and -0.02 (-0.05, -0.00) to -0.07 (-0.09, -0.06) in aunts/uncles and their partners. The association in mothers was stronger than fathers, but it was also stronger in aunts/uncles than their partners. Profound associations between birthweight and CVD risk factors in extended family members were observed that go beyond the expected genetic similarities in pedigrees, suggesting that mechanisms like environmental factors, assortative mating, and genetic nurturing may explain these associations.

Estimating the influence of body mass index (BMI) on mortality using offspring BMI as an instrumental variable.

OBJECTIVE: High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here, we use information from the offspring to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality. METHODS: The analyses were based on information on 9674 offspring-mother and 9096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI-mortality associations were analysed using conventional methods and using offspring BMI as a proxy, or instrument, for their parents' BMI. RESULTS: In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (Pcurvature < 0.001), while offspring BMI had linear associations with parental mortality (Ptrend < 0.001, Pcurvature > 0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes [mothers: HR per SD of BMI 1.43 (95% CI 1.21-1.69), fathers: HR 1.17 (1.00-1.36)] and from coronary heart disease [mothers: HR 1.65 (1.15-2.36), fathers: HR 1.51 (1.17-1.97)]. These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking. CONCLUSIONS: Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies.

Instrumental variable analysis using offspring BMI in childhood as an indicator of parental BMI in relation to mortality.

Childhood BMI shows associations with adult mortality, but these may be influenced by effects of ill health in childhood on BMI and later mortality. To avoid this, we used offspring childhood BMI as an instrumental variable (IV) for own BMI in relation to mortality and compared it with conventional associations of own childhood BMI and own mortality. We included 36,097 parent-offspring pairs with measured heights and weights from the Copenhagen School Health Records Register and register-based information on death. Hazard ratios (HR) were estimated using adjusted Cox regression models. For all-cause mortality, per zBMI at age 7 the conventional HR = 1.07 (95%CI: 1.04-1.09) in women and 1.02 (95%CI: 0.92-1.14) in men, whereas the IV HR = 1.23 (95%CI: 1.15-1.32) in women and 1.05 (95%CI: 0.94-1.17) in men. Per zBMI at age 13, the conventional HR = 1.11 (95%CI: 1.08-1.15) in women and 1.03 (95%CI: 0.99-1.06) in men, whereas the IV HR = 1.30 (95%CI: 1.19-1.42) in women and 1.15 (95%CI: 1.04-1.29) in men. Only conventional models showed indications of J-shaped associations. Our IV analyses suggest that there is a causal relationship between BMI and mortality that is positive at both high and low BMI values.

Body muscle gain and markers of cardiovascular disease susceptibility in young adulthood: A cohort study.

BACKGROUND: The potential benefits of gaining body muscle for cardiovascular disease (CVD) susceptibility, and how these compare with the potential harms of gaining body fat, are unknown. We compared associations of early life changes in body lean mass and handgrip strength versus body fat mass with atherogenic traits measured in young adulthood. METHODS AND FINDINGS: Data were from 3,227 offspring of the Avon Longitudinal Study of Parents and Children (39% male; recruited in 1991-1992). Limb lean and total fat mass indices (kg/m2) were measured using dual-energy X-ray absorptiometry scans performed at age 10, 13, 18, and 25 y (across clinics occurring from 2001-2003 to 2015-2017). Handgrip strength was measured at 12 and 25 y, expressed as maximum grip (kg or lb/in2) and relative grip (maximum grip/weight in kilograms). Linear regression models were used to examine associations of change in standardised measures of these exposures across different stages of body development with 228 cardiometabolic traits measured at age 25 y including blood pressure, fasting insulin, and metabolomics-derived apolipoprotein B lipids. SD-unit gain in limb lean mass index from 10 to 25 y was positively associated with atherogenic traits including very-low-density lipoprotein (VLDL) triglycerides. This pattern was limited to lean gain in legs, whereas lean gain in arms was inversely associated with traits including VLDL triglycerides, insulin, and glycoprotein acetyls, and was also positively associated with creatinine (a muscle product and positive control). Furthermore, this pattern for arm lean mass index was specific to SD-unit gains occurring between 13 and 18 y, e.g., -0.13 SD (95% CI -0.22, -0.04) for VLDL triglycerides. Changes in maximum and relative grip from 12 to 25 y were both positively associated with creatinine, but only change in relative grip was also inversely associated with atherogenic traits, e.g., -0.12 SD (95% CI -0.18, -0.06) for VLDL triglycerides per SD-unit gain. Change in fat mass index from 10 to 25 y was more strongly associated with atherogenic traits including VLDL triglycerides, at 0.45 SD (95% CI 0.39, 0.52); these estimates were directionally consistent across sub-periods, with larger effect sizes with more recent gains. Associations of lean, grip, and fat measures with traits were more pronounced among males. Study limitations include potential residual confounding of observational estimates, including by ectopic fat within muscle, and the absence of grip measures in adolescence for estimates of grip change over sub-periods. CONCLUSIONS: In this study, we found that muscle strengthening, as indicated by grip strength gain, was weakly associated with lower atherogenic trait levels in young adulthood, at a smaller magnitude than unfavourable associations of fat mass gain. Associations of muscle mass gain with such traits appear to be smaller and limited to gains occurring in adolescence. These results suggest that body muscle is less robustly associated with markers of CVD susceptibility than body fat and may therefore be a lower-priority intervention target.

Association of physical activity intensity and bout length with mortality: An observational study of 79,503 UK Biobank participants.

BACKGROUND: Spending more time active (and less sedentary) is associated with health benefits such as improved cardiovascular health and lower risk of all-cause mortality. It is unclear whether these associations differ depending on whether time spent sedentary or in moderate-vigorous physical activity (MVPA) is accumulated in long or short bouts. In this study, we used a novel method that accounts for substitution (i.e., more time in MVPA means less time sleeping, in light activity or sedentary) to examine whether length of sedentary and MVPA bouts associates with all-cause mortality. METHODS AND FINDINGS: We used data on 79,503 adult participants from the population-based UK Biobank cohort, which recruited participants between 2006 and 2010 (mean age at accelerometer wear 62.1 years [SD = 7.9], 54.5% women; mean length of follow-up 5.1 years [SD = 0.73]). We derived (1) the total time participants spent in activity categories-sleep, sedentary, light activity, and MVPA-on average per day; (2) time spent in sedentary bouts of short (1 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration; and (3) MVPA bouts of very short (1 to 9 minutes), short (10 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration. We used Cox proportion hazards regression to estimate the association of spending 10 minutes more average daily time in one activity or bout length category, coupled with 10 minutes less time in another, with all-cause mortality. Those spending more time in MVPA had lower mortality risk, irrespective of whether this replaced time spent sleeping, sedentary, or in light activity, and these associations were of similar magnitude (e.g., hazard ratio [HR] 0.96 [95% CI: 0.94, 0.97; P < 0.001] per 10 minutes more MVPA, coupled with 10 minutes less light activity per day). Those spending more time sedentary had higher mortality risk if this replaced light activity (HR 1.02 [95% CI: 1.01, 1.02; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less light activity per day) and an even higher risk if this replaced MVPA (HR 1.06 [95% CI: 1.05, 1.08; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less MVPA per day). We found little evidence that mortality risk differed depending on the length of sedentary or MVPA bouts. Key limitations of our study are potential residual confounding, the limited length of follow-up, and use of a select sample of the United Kingdom population. CONCLUSIONS: We have shown that time spent in MVPA was associated with lower mortality, irrespective of whether it replaced time spent sleeping, sedentary, or in light activity. Time spent sedentary was associated with higher mortality risk, particularly if it replaced MVPA. This emphasises the specific importance of MVPA. Our findings suggest that the impact of MVPA does not differ depending on whether it is obtained from several short bouts or fewer longer bouts, supporting the recent removal of the requirement that MVPA should be accumulated in bouts of 10 minutes or more from the UK and the United States policy. Further studies are needed to investigate causality and explore health outcomes beyond mortality.

Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics.

BACKGROUND: Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (1H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations). RESULTS: At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides-males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion. CONCLUSIONS: Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.

Estimating the causal effect of BMI on mortality risk in people with heart disease, diabetes and cancer using Mendelian randomization.

BACKGROUND: Observational data have reported that being overweight or obese, compared to being normal weight, is associated with a lower risk for death - the "obesity paradox". We used Mendelian randomization (MR) to estimate causal effects of body mass index (BMI) on mortality risks in people with coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) or malignancy in whom this paradox has been often reported. METHODS: We studied 457,746 White British UK Biobank participants including three subgroups with T2DM (n = 19,737), CHD (n = 21,925) or cancer (n = 42,612) at baseline and used multivariable-adjusted Cox models and MR approaches to describe relationships between BMI and mortality risk. RESULTS: Observational Cox models showed J-shaped relationships between BMI and mortality risk including within disease subgroups in which the BMI values associated with minimum mortality risk were within overweight/obese ranges (26.5-32.5 kg/m2). In all participants, MR analyses showed a positive linear causal effect of BMI on mortality risk (HR for mortality per unit higher BMI: 1.05; 95% CI: 1.03-1.08), also evident in people with CHD (HR: 1.08; 95% CI: 1.01-1.14). Point estimates for hazard ratios across all BMI values in participants with T2DM and cancer were consistent with overall positive linear effects but confidence intervals included the null. CONCLUSION: These data support the idea that population efforts to promote intentional weight loss towards the normal BMI range would reduce, not enhance, mortality risk in the general population including, importantly, individuals with CHD.

Early Metabolic Features of Genetic Liability to Type 2 Diabetes: Cohort Study With Repeated Metabolomics Across Early Life.

OBJECTIVE: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life. RESEARCH DESIGN AND METHODS: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, and others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults. RESULTS: At age 8 years, associations were most evident for type 2 diabetes liability (per SD higher) with lower lipids in HDL subtypes (e.g., -0.03 SD [95% CI -0.06, -0.003] for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD; 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched-chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability. CONCLUSIONS: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.

GOLD Classifications, COPD Hospitalization, and All-Cause Mortality in Chronic Obstructive Pulmonary Disease: The HUNT Study.

Purpose: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published three classifications of COPD from 2007 to 2017. No studies have investigated the ability of these classifications to predict COPD-related hospitalizations. We aimed to compare the discrimination ability of the GOLD 2007, 2011, and 2017 classifications to predict COPD hospitalization and all-cause mortality. Patients and Methods: We followed 1300 participants with COPD aged ≥40 years who participated in the HUNT Study (1995-1997) through to December 31, 2015. Survival analysis and time-dependent area under receiver operating characteristics curves (AUC) were used to compare the discrimination abilities of the GOLD classifications. Results: Of the 1300 participants, 522 were hospitalized due to COPD and 896 died over 20.4 years of follow-up. In adjusted models, worsening GOLD 2007, GOLD 2011, or GOLD 2017 categories were associated with higher hazards for COPD hospitalization and all-cause mortality, except for the GOLD 2017 classification and all-cause mortality (ptrend=0.114). In crude models, the AUCs (95% CI) for the GOLD 2007, GOLD 2011, and GOLD 2017 for COPD hospitalization were 63.1 (58.7-66.9), 60.9 (56.1-64.4), and 56.1 (54.0-58.1), respectively, at 20-years' follow-up. Corresponding estimates for all-cause mortality were 57.0 (54.8-59.1), 54.1 (52.1-56.0), and 52.6 (51.0-54.3). The differences in AUCs between the GOLD classifications to predict COPD hospitalization and all-cause mortality were constant over the follow-up time. Conclusion: The GOLD 2007 classification was better than the GOLD 2011 and 2017 classifications at predicting COPD hospitalization and all-cause mortality.

Birthweight in offspring and cardiovascular mortality in their parents, aunts and uncles: a family-based cohort study of 1.35 million births.

BACKGROUND: A link between suboptimal fetal growth and higher risk of cardiovascular disease (CVD) is well documented. It has been difficult to assess the contribution of environmental versus genetic factors to the association, as these factors are closely connected in nuclear families. We investigated the association between offspring birthweight and CVD mortality in parents, aunts and uncles, and examined whether these associations are explained by CVD risk factors. METHODS: We linked Norwegian data from the Medical Birth Registry, the Cause of Death Registry and cardiovascular surveys. A total of 1 353 956 births (1967-2012) were linked to parents and one maternal and one paternal aunt/uncle. Offspring birthweight and CVD mortality association among all relationships was assessed by hazard ratios (HR) from Cox regressions. The influence of CVD risk factors on the associations was examined in a subgroup. RESULTS: Offspring birthweight was inversely associated with CVD mortality among parents and aunts/uncles. HR of CVD mortality for one standard deviation (SD) increase in offspring birthweight was 0.72 (0.69-0.75) in mothers and 0.89 (0.86-0.92) in fathers. In aunts/uncles, the HRs were between 0.90 (0.86-0.95) and 0.93 (0.91-0.95). Adjustment for CVD risk factors in a subgroup attenuated all the associations. CONCLUSIONS: Birthweight was associated with increased risk of CVD in parents and in aunts/uncles. These associations were largely explained by CVD risk factors. Our findings suggest that associations between offspring birthweight and CVD in adult relatives involve both behavioural variables (especially smoking) and shared genetics relating to established CVD risk factors.

Comparison of pre- and post-bronchodilator lung function as predictors of mortality: The HUNT Study.

BACKGROUND AND OBJECTIVE: Post-bronchodilator (BD) lung function is recommended for the diagnosis of chronic obstructive pulmonary disease (COPD). However, often only pre-BD lung function is used in clinical practice or epidemiological studies. We aimed to compare the discrimination ability of pre-BD and post-BD lung function to predict all-cause mortality. METHODS: Participants aged ≥40 years with airflow limitation (n = 2538) and COPD (n = 1262) in the second survey of the Nord-Trøndelag Health Study (HUNT2, 1995-1997) were followed up until 31 December 2015. Survival analysis and time-dependent area under the receiver operating characteristic curves (AUC) were used to compare the discrimination ability of pre-BD and post-BD lung function (percent-predicted forced expiratory volume in the first second (FEV1 ) (ppFEV1 ), FEV1 z-score, FEV1 quotient (FEV1 Q), modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) categories or GOLD grades). RESULTS: Among 2538 participants, 1387 died. The AUC for pre-BD and post-BD ppFEV1 to predict mortality were 60.8 and 61.8 (P = 0.005), respectively, at 20 years' follow-up. The corresponding AUC for FEV1 z-score were 58.5 and 60.4 (P < 0.001), for FEV1 Q were 68.7 and 70.1 (P = 0.002) and for modified GOLD categories were 62.3 and 64.5 (P < 0.001). Among participants with COPD, the AUC for pre-BD and post-BD ppFEV1 were 57.0 and 58.8 (P < 0.001), respectively. The corresponding AUC for FEV1 z-score were 53.1 and 55.8 (P < 0.001), for FEV1 Q were 63.6 and 65.1 (P = 0.037) and for GOLD grades were 56.0 and 57.0 (P = 0.268). CONCLUSION: Mortality was better predicted by post-BD than by pre-BD lung function; however, they differed only by a small margin. The discrimination ability using GOLD grades among COPD participants was similar.

Associations of parental age with offspring all-cause and cause-specific adult mortality.

People are having children later in life. The consequences for offspring adult survival have been little studied due to the need for long follow-up linked to parental data and most research has considered offspring survival only in early life. We used Swedish registry data to examine all-cause and cause-specific adult mortality (293,470 deaths among 5,204,433 people, followed up to a maximum of 80 years old) in relation to parental age. For most common causes of death adult survival was improved in the offspring of older parents (HR for all-cause survival was 0.96 (95% CI: 0.96, 0.97) and 0.98 (0.97, 0.98) per five years of maternal and paternal age, respectively). The childhood environment provided by older parents may more than compensate for any physiological disadvantages. Within-family analyses suggested stronger benefits of advanced parental age. This emphasises the importance of secular trends; a parent's later children were born into a wealthier, healthier world. Sibling-comparison analyses can best assess individual family planning choices, but our results suggested a vulnerability to selection bias when there is extensive censoring. We consider the numerous causal and non-causal mechanisms which can link parental age and offspring survival, and the difficulty of separating them with currently available data.

Variation of all-cause and cause-specific mortality with body mass index in one million Swedish parent-son pairs: An instrumental variable analysis.

BACKGROUND: High body mass index (BMI) is associated with mortality, but the pervasive problem of confounding and reverse causality in observational studies limits inference about the direction and magnitude of causal effects. We aimed to obtain estimates of the causal association of BMI with all-cause and cause-specific mortality. METHODS AND FINDINGS: In a record-linked, intergenerational prospective study from the general population of Sweden, we used two-sample instrumental variable (IV) analysis with data from 996,898 fathers (282,407 deaths) and 1,013,083 mothers (153,043 deaths) and their sons followed up from January 1, 1961, until December 31, 2004. Sons' BMI was used as the instrument for parents' BMI to compute hazard ratios (HRs) for risk of mortality per standard deviation (SD) higher parents' BMI. Using offspring exposure as an instrument for parents' exposure is unlikely to be affected by reverse causality (an important source of bias in this context) and reduces confounding. IV analyses supported causal associations between higher BMI and greater risk of all-cause mortality (HR [95% confidence interval (CI)] per SD higher fathers' BMI: 1.29 [1.26-1.31] and mothers' BMI: 1.39 [1.35-1.42]) and overall cancer mortality (HR per SD higher fathers' BMI: 1.20 [1.16-1.24] and mothers' BMI: 1.29 [1.24-1.34]), including 9 site-specific cancers in men (bladder, colorectum, gallbladder, kidney, liver, lung, lymphatic system, pancreas, and stomach) and 11 site-specific cancers in women (gallbladder, kidney, liver, lung, lymphatic system, ovaries, pancreas, stomach, uterus, cervix, and endometrium). There was evidence supporting causal associations between higher BMI in mothers and greater risk of mortality from kidney disease (HR: 2.17 [1.68-2.81]) and lower risk of mortality from suicide (HR: 0.77 [0.65-0.90]). In both sexes, there was evidence supporting causal associations between higher BMI and mortality from cardiovascular diseases (CVDs), stroke, diabetes, and respiratory diseases. We were unable to test the association between sons' and mothers' BMIs (as mothers' data were unavailable) or whether the instrument was independent of unmeasured or residual confounding; however, the associations between parents' mortality and sons' BMI were negligibly influenced by adjustment for available confounders. CONCLUSIONS: Consistent with previous large-scale meta-analyses and reviews, results supported the causal role of higher BMI in increasing the risk of several common causes of death, including cancers with increasing global incidence. We also found positive effects of BMI on mortality from respiratory disease, prostate cancer, and lung cancer, which has been inconsistently reported in the literature, suggesting that the causal role of higher BMI in mortality from these diseases may be underestimated. Furthermore, we expect different patterns of bias in the current observational and IV analyses; therefore, the similarities between our findings from both methods increases confidence in the results. These findings support efforts to understand the mechanisms underpinning these effects to inform targeted interventions and develop population-based strategies to reduce rising obesity levels for disease prevention.

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable.

High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son's SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents' cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.