Objective: To use two-sample Mendelian randomisation (MR) to study the causal effect of body mass index (BMI) on Parkinson’s disease (PD).

Background: Both positive and negative associations between BMI and PD have been reported in observational studies, but it has been difficult to establish causality because of the possibility of residual confounding or reverse causation. To our knowledge, MR, the use of genetic instrumental variables to explore causal effects, has not previously been used to test the effect of BMI on PD.

Methods: Two-sample MR was undertaken using genome-wide association study data. The associations between the genetic instruments and BMI were obtained from the GIANT consortium (1) and consisted of the per-allele difference in mean BMI for 77 independent variants that reached genome-wide significance. The per-allele difference in log-odds of PD for each of these variants was estimated from a recent meta-analysis (2), which included 13,708 cases of PD and 95,282 controls. The inverse variance weighted method was used to estimate a pooled odds ratio (OR) for the effect of a 5kg/m2 increase in BMI on PD. Evidence of directional pleiotropy averaged across all variants was sought using MR-Egger regression. Frailty simulations were used to assess whether causal associations were affected by mortality selection.

Results: A genetically related 5kg/m2 increase in BMI was associated with a reduced risk of PD (OR 0·82, 95% CI 0·69-0·98). MR-Egger regression gave similar results (OR 0·76, 95% CI 0·51-1·14), providing evidence against directional pleiotropy (intercept 0·002, p-value=0·654). Frailty analysis indicated that the observed negative association between BMI and PD may have been biased by a negative association between BMI and survival, but this did not fully explain the estimated causal effect.

Conclusions: In this large study using two-sample MR, we found evidence to suggest that increased BMI may be protective against risk of PD. The mechanism underlying this protective effect warrants further study.

References: 1) Locke AE, et al. Nature 2015; 518: 197–206.

2) Nalls MA, et al. Nat Genet 2014; 46: 989–993.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/increased-bmi-may-protect-against-parkinsons-disease-evidence-from-a-mendelian-randomisation-study/