Background
Obesity is a worldwide epidemic that has been associated with an increased risk of a plurality of chronic diseases in traditional observational studies [
1‐
6]. These observational findings [
1‐
6] may represent the causal effect of obesity on disease risk or confounding from other risk factors, such as a poor diet and physical inactivity. During the last years, an increasing number of Mendelian randomization (MR) studies of adiposity, mostly defined by body mass index (BMI), in relation to chronic diseases have been published [
7‐
53]. MR is an instrumental variable analysis that exploits genetic variants with a robust impact on the exposure (e.g., BMI) as proxy markers for the exposure to test whether the exposure has a causal relationship with disease risk [
54]. Compared with conventional observational studies, MR studies are less susceptible to confounding as genes are randomly assorted when passed from parents to descendants [
54]. Additionally, MR studies are not biased by reverse causality as genes are constant and not modified by disease development.
The aim of this study was to conduct a systematic review and meta-analyses of MR studies to determine the causal role of excess adiposity in chronic diseases. Meta-analyses were performed using results from published MR studies and complemented with results from de novo MR analyses of pertinent disease outcomes in the FinnGen consortium.
Discussion
This contemporary meta-analysis of MR studies of genetically predicted BMI in relation to 56 chronic diseases provides evidence in support of causal associations of excess adiposity with increased risk of type 2 diabetes mellitus, 14 circulatory system diseases, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, multiple sclerosis, and cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, MR evidence indicates that high BMI is associated with a decreased risk of breast, prostate, and non-melanoma skin cancer, Dupuytren’s disease, and osteoporosis, and not likely associated with risk of Alzheimer disease, amyotrophic lateral sclerosis, or Parkinson’s disease.
This meta-analysis of MR studies found consistent associations of higher genetically predicted BMI and increased risk of type 2 diabetes mellitus and cardiovascular diseases. However, conflicting results were found for adulthood BMI in relation to type 1 diabetes mellitus. The inconsistent results might be related to different ages at onset of type 1 diabetes mellitus in the UK Biobank and FinnGen populations or that genetic instruments for adulthood BMI rather than childhood BMI were used. An MR study of genetically predicted childhood BMI showed a positive association with childhood-onset (<17 years) type 1 diabetes mellitus (
OR 1.32,
95% CI 1.06–1.64 per
SD score increase in BMI based on 32 SNPs) [
62]. Excess adiposity may increase the risk of type 2 diabetes mellitus and cardiovascular diseases by increasing fasting glucose, insulin, and triglyceride levels; raising blood pressure; and promoting systemic inflammation [
63‐
65]. An MR study based on consortia data found that the genetic association of BMI with risk of coronary artery disease, peripheral artery disease, and stroke was partly mediated by systolic blood pressure and type 2 diabetes mellitus, but not materially mediated by lipids or smoking [
19].
Higher genetically predicted BMI was associated with increased risk of several diseases of the respiratory, digestive, and musculoskeletal systems, including asthma, gallbladder disease, diverticular disease, nonalcoholic fatty liver disease, gout, osteoarthritis, and rheumatoid arthritis. The associations may be related to an obesity-related reduction in lung volume (for asthma), joint loading (for osteoarthritis), and alterations in microbiota composition, inflammatory mediators, and hormone levels. In contrast, higher genetically predicted BMI was associated with a modest lower risk of osteoporosis, possibly explained by mechanical stresses mediated through gravitational action. This finding confirms previous MR studies that have shown a positive association between genetically predicted BMI and bone mineral density [
66,
67]. Genetically predicted BMI was also inversely associated with the risk of Dupuytren’s disease in an MR study based on data from a genome-wide association study on this outcome [
30]. The mechanism behind this association is unclear but might be related to lower testosterone levels with increasing BMI [
30]. For the two inflammatory bowel diseases, the direction of the association with genetically predicted BMI differed for Crohn’s disease (positive association) and ulcerative colitis (inverse association). A previous meta-analysis of observational studies found that BMI was positively associated with the risk of Crohn’s disease but unrelated to ulcerative colitis [
68]. Hence, the observed inverse association between genetically predicted BMI and ulcerative colitis in the present meta-analysis of two MR studies may be a spurious finding. In fact, the inverse association was only significant in the IBD consortium but not in the FinnGen consortium.
This meta-analysis of MR studies provided evidence that excess adiposity increases the risk of multiple sclerosis but not Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s disease. If anything, a suggestive inverse association was observed between genetically predicted BMI and Parkinson’s disease. This finding is consistent with the results of a previous meta-analysis that found that being underweight was associated with an increased risk of Parkinson’s disease [
69].
The opposite direction of the associations of genetically predicted BMI with different cancers suggests different causal pathways for BMI and various cancers. The increased risk of cancers of the digestive system, uterus, kidney, and bladder may be mediated by alterations in insulin signaling, growth factors, adipose tissue-derived inflammation, and hormone levels. Higher genetically predicted BMI has been shown to relate to lower serum testosterone levels [
70], and testosterone levels are positively associated with risk of breast, prostate, and skin cancer [
71,
72]. Thus, the observed inverse associations of genetically predicted BMI with these cancers might, at least in part, be explained by lower testosterone levels in overweight and obese individuals. In premenopausal women, high BMI may lower breast cancer risk via decreased estradiol levels [
73].
Heterogeneity was observed between estimates from individual studies in analyses of genetically predicted BMI and several disease outcomes (e.g., diabetes, aortic valve stenosis, atrial fibrillation, hypertension, and stomach, endometrial, bladder, head and neck, and lung cancer). The detected heterogeneity was mainly caused by the different magnitude of the associations across studies and may be related to different genetic instruments used or to different study populations with different characteristics.
A strength of MR studies is that confounding and reverse causation bias are reduced as BMI is proxied by genetic variants that generally are not related to self-selected behaviors and environmental exposures and are not modified by disease development. The validity of MR findings relies on the absence of pleiotropy (i.e., where a genetic variant is associated with more than one phenotype). Researchers of most MR studies included in the meta-analysis performed sensitivity analyses and found limited evidence that the associations were biased by pleiotropy. Another limitation in MR studies of obesity and other harmful exposures in relation to late-onset diseases is competing risk bias, which is a potential type of survival bias. It cannot be ruled out that this bias might have affected the results in some of the studies. A further shortcoming is that most MR studies comprised individuals of European ancestry and therefore cannot infer causality of the role of excess adiposity in chronic diseases in non-European populations.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.