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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

LanguageEnglish
Pages834-848
Number of pages15
JournalInternational journal of epidemiology
Volume48
Issue number3
DOIs
Publication statusPublished - 1 Jun 2019

Keywords

  • Body mass index
  • Mendelian randomization
  • UK Biobank
  • depression

ASJC Scopus subject areas

  • Epidemiology

Cite this

Tyrrell, Jessica ; Gebremichael, Anwar Mulugeta ; Wood, Andrew R. ; Zhou, Ang ; Beaumont, Robin N. ; Tuke, Marcus A. ; Jones, Samuel E. ; Ruth, Katherine S. ; Yaghootkar, Hanieh ; Sharp, Seth ; Thompson, William D. ; Ji, Yingjie ; Harrison, Jamie ; Freathy, Rachel M. ; Murray, Anna ; Weedon, Michael N. ; Lewis, Cathryn ; Frayling, Timothy M. ; Hypponen, Elina. / Using genetics to understand the causal influence of higher BMI on depression. In: International journal of epidemiology. 2019 ; Vol. 48, No. 3. pp. 834-848.
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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",
author = "Jessica Tyrrell and Gebremichael, {Anwar Mulugeta} and Wood, {Andrew R.} and Ang Zhou and Beaumont, {Robin N.} and Tuke, {Marcus A.} and Jones, {Samuel E.} and Ruth, {Katherine S.} and Hanieh Yaghootkar and Seth Sharp and Thompson, {William D.} and Yingjie Ji and Jamie Harrison and Freathy, {Rachel M.} and Anna Murray and Weedon, {Michael N.} and Cathryn Lewis and Frayling, {Timothy M.} and Elina Hypponen",
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Tyrrell, J, Gebremichael, AM, Wood, AR, Zhou, A, Beaumont, RN, Tuke, MA, Jones, SE, Ruth, KS, Yaghootkar, H, Sharp, S, Thompson, WD, Ji, Y, Harrison, J, Freathy, RM, Murray, A, Weedon, MN, Lewis, C, Frayling, TM & Hypponen, E 2019, 'Using genetics to understand the causal influence of higher BMI on depression', International journal of epidemiology, vol. 48, no. 3, pp. 834-848. https://doi.org/10.1093/ije/dyy223

Using genetics to understand the causal influence of higher BMI on depression. / Tyrrell, Jessica; Gebremichael, Anwar Mulugeta; Wood, Andrew R.; Zhou, Ang; Beaumont, Robin N.; Tuke, Marcus A.; Jones, Samuel E.; Ruth, Katherine S.; Yaghootkar, Hanieh; Sharp, Seth; Thompson, William D.; Ji, Yingjie; Harrison, Jamie; Freathy, Rachel M.; Murray, Anna; Weedon, Michael N.; Lewis, Cathryn; Frayling, Timothy M.; Hypponen, Elina.

In: International journal of epidemiology, Vol. 48, No. 3, 01.06.2019, p. 834-848.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Using genetics to understand the causal influence of higher BMI on depression

AU - Tyrrell, Jessica

AU - Gebremichael, Anwar Mulugeta

AU - Wood, Andrew R.

AU - Zhou, Ang

AU - Beaumont, Robin N.

AU - Tuke, Marcus A.

AU - Jones, Samuel E.

AU - Ruth, Katherine S.

AU - Yaghootkar, Hanieh

AU - Sharp, Seth

AU - Thompson, William D.

AU - Ji, Yingjie

AU - Harrison, Jamie

AU - Freathy, Rachel M.

AU - Murray, Anna

AU - Weedon, Michael N.

AU - Lewis, Cathryn

AU - Frayling, Timothy M.

AU - Hypponen, Elina

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - Body mass index

KW - Mendelian randomization

KW - UK Biobank

KW - depression

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