Phenome-Wide Analysis to Establish Causal Evidence for an Association Between Body Mass Index and Multiple Disease Outcomes in the UK Biobank

Abstract

Background: Mendelian randomization (MR) allows the testing of causal effects in situations where clinical trials are challenging to conduct. In this phenome-wide association MR study (MR-PheWAS), we sought to establish the full extent of comorbidity risk associated with high body mass index (BMI). Methods: Analyses of BMI-genetic risk score (GRS) were conducted against 925 registry linked disease outcomes in 337,536 participants of the UK Biobank. Disease associations passing stringent correction for multiple testing were explored to establish causal relationship with BMI using several complementary MR approaches. Findings: After correction for multiple testing (P<10-5), PheWAS suggested associations between BMI-GRS and 58 outcomes, with 30 distinct disease associations supported by the MR analyses. In inverse-variance weighted MR, genetically instrumented BMI was associated with endocrine disorders (type 2 diabetes odds ratio 2·72, 95%CI 2·33-3·291; type 1 diabetes 2·11, 1·62-2·76; hypothyroidism 1·46, 1·25-1·70), circulatory diseases (phlebitis/thrombophlebitis 1·96, 1·53-2·51; cardiomegaly 1·89, 1·39-2·57; congestive heart failure 1·68, 1·35-2·09, hypertension 1·55, 1·37-1·76; ischemic heart disease 1·31,1·13-1·52; cardiac dysrhythmias 1·25, 1·14-1·37), and inflammatory or dermatologic conditions (superficial cellulitis and abscess 2·00, 1·72-2·23; chronic ulcers of leg and foot 3·37 ,2·17-5·25; gangrene 4·99,2·54-9·82; atopy 2·24, 1·53- 3·28). BMI-GRS was associated with renal failure, osteoarthrosis, neurological (insomnia, peripheral nerve disorders) and respiratory diseases (asthma, chronic bronchitis), as well as structural problems (hernias, knee derangement), and the need for chemotherapy treatment. Interpretation: The burden of comorbidity associated with high BMI is enormous, with our study guiding comorbidity prevention, and highlighting the wide-spread economic and health implications by the ongoing obesity epidemic. Funding Statement: National Health and Medical Research Council. Declaration of Interests: The authors state: none. Ethics Approval Statement: The UK Biobank study was approved by the National Information Governance Board for Health and Social Care and North West Multicentre Research Ethics Committee (11/NW/0382).