Abstract
Aims/hypothesisThe aim of this study was to use Mendelian randomisation (MR) to identify the causal risk factors for type 2 diabetes.MethodsWe first conducted a review of meta-analyses and review articles to pinpoint possible risk factors for type 2 diabetes. Around 170 possible risk factors were identified of which 97 risk factors with available genetic instrumental variables were included in MR analyses. To reveal more risk factors that were not included in our MR analyses, we conducted a review of published MR studies of type 2 diabetes. For our MR analyses, we used summary-level data from the DIAbetes Genetics Replication And Meta-analysis consortium (74,124 type 2 diabetes cases and 824,006 controls of European ancestry). Potential causal associations were replicated using the FinnGen consortium (11,006 type 2 diabetes cases and 82,655 controls of European ancestry). The inverse-variance weighted method was used as the main analysis. Multivariable MR analysis was used to assess whether the observed associations with type 2 diabetes were mediated by BMI. We used the Benjamini–Hochberg method that controls false discovery rate for multiple testing.ResultsWe found evidence of causal associations between 34 exposures (19 risk factors and 15 protective factors) and type 2 diabetes. Insomnia was identified as a novel risk factor (OR 1.17 [95% CI 1.11, 1.23]). The other 18 risk factors were depression, systolic BP, smoking initiation, lifetime smoking, coffee (caffeine) consumption, plasma isoleucine, valine and leucine, liver alanine aminotransferase, childhood and adulthood BMI, body fat percentage, visceral fat mass, resting heart rate, and four plasma fatty acids. The 15 exposures associated with a decreased risk of type 2 diabetes were plasma alanine, HDL- and total cholesterol, age at menarche, testosterone levels, sex hormone binding globulin levels (adjusted for BMI), birthweight, adulthood height, lean body mass (for women), four plasma fatty acids, circulating 25-hydroxyvitamin D and education years. Eight associations remained after adjustment for adulthood BMI. We additionally identified 21 suggestive risk factors (p < 0.05), such as alcohol consumption, breakfast skipping, daytime napping, short sleep, urinary sodium, and certain amino acids and inflammatory factors.Conclusions/interpretationThe present study verified several previously reported risk factors and identified novel potential risk factors for type 2 diabetes. Prevention strategies for type 2 diabetes should be considered from multiple perspectives on obesity, mental health, sleep quality, education level, birthweight and smoking.Graphical abstract
Highlights
Type 2 diabetes is a global public health issue, affecting 9 in 100 adults worldwide in 2015 according to the International Diabetes Federation [1, 2]
We conducted a review of published Mendelian randomisation (MR) studies of type 2 diabetes to reveal more risk factors that were not included in the present study
Summary of results of this MR investigation and review of previous MR studies Among 97 exposures examined in this MR investigation (Table 1 and ESM Table 6), 29 were nominally associated with type 2 diabetes (p < 0.05) of which 20 were associated with type 2 diabetes after Benjamini– Hochberg adjustment for multiple comparisons (ESM Tables 5 and 6)
Summary
Type 2 diabetes is a global public health issue, affecting 9 in 100 adults worldwide in 2015 according to the International Diabetes Federation [1, 2]. The increasing prevalence of type 2 diabetes along with severe complications cause an immense disease and economic burden [1, 3]. It is important to better understand the aetiological basis of type 2 diabetes and establish prevention strategies. Reviews of observational studies have revealed a large number of possible risk factors for type 2 diabetes covering health status, dietary and lifestyle factors, environmental factors, and different biomarkers [4,5,6]. Whether the reported associations are causal remains unclear due to potential methodological limitations in the observational studies, such as confounding and reverse causality. For certain exposures with defined detrimental influences on human health, such as smoking and heavy alcohol drinking, it is unfeasible to determine their causal associations with type 2 diabetes in an experimental setting
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