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. 2019 Jun 1;48(3):834-848.
doi: 10.1093/ije/dyy223.

Using genetics to understand the causal influence of higher BMI on depression

Jessica Tyrrell  1 , Anwar Mulugeta  2 , Andrew R Wood  1 , Ang Zhou  2 , Robin N Beaumont  1 , Marcus A Tuke  1 , Samuel E Jones  1 , Katherine S Ruth  1 , Hanieh Yaghootkar  1 , Seth Sharp  1 , William D Thompson  1 , Yingjie Ji  1 , Jamie Harrison  1 , Rachel M Freathy  1 , Anna Murray  1 , Michael N Weedon  1 , Cathryn Lewis  3 , Timothy M Frayling  1 , Elina Hyppönen  2
Affiliations

Using genetics to understand the causal influence of higher BMI on depression

Jessica Tyrrell et al. Int J Epidemiol. .

Abstract

Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women.

Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways.

Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence.

Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

Keywords: Body mass index; Mendelian randomization; UK Biobank; depression.

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Figures

Figure 1.
Figure 1.
The principles of Mendelian randomization and key MR assumptions which are: (i) the genetic instrument (Z) is robustly related to the risk factor of interest (X); (ii) Z is not associated with confounders (C) of the X-outcome (Y) association; and (iii) there is no path from Z to Y other than through X (part a). Part b shows how this may be violated.
Figure 2.
Figure 2.
Flow chart explaining the derivation of depression cases and controls in the UK Biobank.
Figure 3.
Figure 3.
Forest plot of the observational and genetic associations between a 1-SD higher BMI and the odds of depression. The plots display the observational association (Observational) and the genetic association using the two-step instrumental variable analysis with the BMI genetic risk score (Genetic 1-sample).
Figure 4.
Figure 4.
Plot of the individual BMI variant—BMI associations from the primary GWAS that did not include UK Biobank against the BMI variant—depression associations on natural log scale (LN(OH)) from related Europeans in the UK Biobank, in: A) all individuals; B) males only; and C) females only. The beta regression coefficients for inverse variance weighted (IVW) instrumental analysis (black solid), Egger-MR (black dash), median-IV (grey solid) and the penalized weight median IV (grey dash) are plotted. The Egger intercept P-value is also given on the plots.
Figure 5.
Figure 5.
Plot of the individual BMI variant—BMI associations from the primary GWAS that did not include UK Biobank against the BMI variant—depression associations on natural log scale (LN(OR)) from the PGC GWAS data excluding the UK Biobank. The beta regression coefficients for inverse variance weighted (IVW) instrumental analysis (black solid), Egger-MR (black dash), median-IV (grey solid) and the penalized weight median IV (grey dash) are plotted.
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