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Higher BMI may protect against Parkinson’s Disease

Stephen Padilla
31 Jul 2017

Higher body mass index (BMI) appears to lower the risk of Parkinson’s Disease (PD), according to a large study using two-sample Mendelian randomization (MR).

“Our analysis indicated a potential causal influence of higher BMI protecting against PD,” researchers said. “A limitation of the approach is that individuals who have higher BMI have a higher risk of earlier mortality, and therefore individuals with lower BMI may be over-represented amongst individuals diagnosed with PD.”

Genome-wide association (GWA) study data were used to carry out two-sample MR. The authors obtained the associations between the genetic instruments and BMI from the GIANT consortium and consisted of the per-allele difference in mean BMI for 77 independent variants that reached genome-wide significance.

A recent meta-analysis involving 13,708 cases of PD and 95,282 controls was used to assess the per-allele difference in log-odds of PD for each of the variants. Researchers then used the inverse-variance weighted method to estimate a pooled odds ratio (OR) for the effect of a 5-kg/m2 higher BMI on PD.

MR-Egger regression was used to seek evidence of directional pleiotropy averaged across all variants, and frailty simulations were applied to assess whether causal associations were affected by mortality selection.

“We used two-sample MR, in which the relationship between genetic variants and BMI was ascertained from one study, and the relationship between the same genetic variants and PD was ascertained from a second study,” researchers noted. “Using this method, one can determine the estimated change in risk of PD per unit change in BMI.”

There was an association between a combined genetic instrumental variables (IV) expected to confer a lifetime exposure of 5-kg/m2 higher BMI and a lower risk of PD (OR, 0.82; 95 percent CI, 0.69 to 0.98). Results were similar with MR-Egger regression, which suggests that directional pleiotropy was not likely to be biasing the result (intercept, 0.002; p=0.654). [PLoS Med 2017;doi:10.1371/journal.pmed.1002314]

“Prior to PD diagnosis, observational studies have found conflicting results with regard to the association between BMI and risk of PD,” researchers said. “The conflicting results may be due to study-specific biases, differential adjustment for confounding factors and use of different cutoffs to define the exposure.” [Acta Neurol Scand 2006;113:278–81; Am J Epidemiol 2004;159:547–55; Pharmacoepiol Drug Saf 2016;25(Suppl 3):105; Am J Epidemiol 2007;166:1186–90; Neurology 2006;67:1955–9]

However, this protective effect of higher BMI could at least be partially generated by survival bias in the PD GWA study, as shown by frailty simulations. Such application of MR has other important limitations, including the inability to analyse nonlinear associations, to undertake subgroup analyses and to gain mechanistic insights.

“Although BMI is a potentially modifiable risk factor for PD, the negative health impacts of raising BMI are likely to be significant, and should be taken into account,” researchers said. “Expected negative effects would include increased risk of type 2 diabetes mellitus, ischaemic heart disease and cancer.”

“Assuming replication of a negative association between BMI and PD, a great deal of further work would be required (including mechanistic insights) before recommending this as a potential intervention against PD, given the wider public health effects,” they added.

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