A genetic predisposition to obesity is randomly allocated, and mendelian randomisation studies exploit this natural experiment to find out if well established associations between obesity and disease are likely to be causal.

The latest study used a genetic variation that increases body mass index (BMI) by 0.36 unit per allele. In analyses pooling 36 observational studies, people with the implicated allele had a small but significantly increased risk of heart failure and the abnormal liver enzymes typical of non-alcoholic fatty liver disease.

As expected, they also had an increased BMI, and it is likely that the extra adiposity causes both heart failure and fatty liver, say the authors.

The authors confirmed similar links between the ‘fat’ allele and diabetes, hypertension, metabolic syndrome, dyslipidaemia and increased C reactive protein, a marker of inflammation. However, the authors could not find a causal association between adiposity and heart disease, possibly because of low power.

genetic predisposition explains only a small fraction of the variation in BMI, so studies have to be very big to find (or rule out) associations with disease.

The authors had data on genotype, BMI and cardiometabolic outcomes in as many as 160,000 people, mostly from Europe. The effect of BMI on most outcomes was similar when estimated with the mendelian randomisation or with traditional observational methods.

Source: PLoS Med 2013;10:e1001474.