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.
Kaitlin Wade and colleagues investigate associations between BMI and cause-specific mortality in a large cohort of parent-son pairs.
Author summary Why was this study done? Whilst high body mass index (BMI) clearly increases the risk of mortality, there have been inconsistencies in the literature, which mainly rely on observational epidemiological studies that are limited in their ability to draw causal inferences. To overcome the pervasive problem of confounding and reverse causation in such studies, we aimed to obtain more reliable causal estimates of the association of BMI and both all-cause and cause-specific mortality using two-sample instrumental variable (IV) analyses. What did the researchers do and find? In a large, record-linked, intergenerational prospective study comprising data from the general population of Sweden from 996,898 fathers (282,407 deaths) and 1,013,082 mothers (153,043 deaths) and their sons, we used sons’ BMI as an instrument for parents’ BMI to compute hazard ratios (HRs) for the risk of mortality per standard deviation (SD) higher parents’ BMI. IV analyses supported the causal role of higher BMI and greater risk of all-cause mortality and mortality from cardiovascular diseases (CVDs), stroke, diabetes, respiratory diseases, and cancer, the latter 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 also evidence supporting a causal association between higher BMI in mothers and greater risk of mortality from kidney disease and lower risk of mortality from suicide. What do these findings mean? For cancer-specific mortality, many IV-derived effect estimates were in the same direction and of greater magnitude as those derived from previous large-scale meta-analyses and reviews focusing on both mortality outcomes and the development of specific cancers. Results also implied a positive effect 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. These results support efforts to reduce obesity levels for disease prevention, particularly cancer.