Higher adiposity and mental health: causal inference using Mendelian randomization

TY - JOUR

T1 - Higher adiposity and mental health: causal inference using Mendelian randomization

AU - Casanova, Francesco

AU - O’Loughlin, Jessica

AU - Beaumont, Robin N

AU - Wood, Andrew R

AU - Watkins, Edward R

AU - Freathy, Rachel M

AU - Hagenaars, Saskia P

AU - Frayling, Timothy M

AU - Yaghootkar, Hanieh

AU - Tyrrell, Jess

N1 - Funding Information: Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079 to J.O., F.C. and J.T.); Wellcome Senior Research Fellowship (WT220390 to R.M.F.). Diabetes UK RD Lawrence fellowship (17/0005594 to H.Y.). Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press.

PY - 2021/12/15

Y1 - 2021/12/15

N2 - Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one-and two-sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß:-0.15, 95%CI:-0.26,-0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being.

AB - Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one-and two-sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß:-0.15, 95%CI:-0.26,-0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being.

KW - Genetics(clinical)

KW - Genetics

KW - Molecular Biology

KW - General Medicine

UR - http://www.scopus.com/inward/record.url?scp=85122315799&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddab204

DO - 10.1093/hmg/ddab204

M3 - Article

SN - 0964-6906

VL - 30

SP - 2371

EP - 2382

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 24

ER -