Higher adiposity and mental health: causal inference using Mendelian randomization

Abstract

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 Randomisation(MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on ten well-validated mental health and wellbeing 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 wellbeing [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 wellbeing scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers wellbeing. 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 wellbeing.

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study

“…Previously, BMI has been identified as a potential pathway to horizontal pleiotropy when using AAM as exposure as a large number of SNPs associated with AAM are also negatively related to BMI ( Day et al, 2017 ). When also considering that a higher BMI is associated with a higher risk for depression ( Casanova et al, 2021 ), BMI is a potential source of horizontal pleiotropy. Moreover, recently, Magnus et al (2020) have shown in their one-sample MR phenome-wide association study with 17,893 health-related traits in the UK Biobank that many phenotype categories, such as sociodemographic characteristics, substance use and addictions, mental health and traumatic events, measures of cognition and aging, blood parameters, and others, might also be relevant in this regard.…”

The Relationship Between Obesity and Depression Is Partly Dependent on Metabolic Health Status: A Nationwide Inpatient Sample Database Study

“…Multiple risk factors, such as gender, family history, psychological stress, and alcohol, have been found to be associated with the occurrence of depression ( 4 , 5 ). As a modifiable risk factor, obesity is considered to be a risk factor for depression ( 6 – 8 ); however, the results remain controversial. A few studies have identified a relationship between obesity and depression only among women ( 9 – 11 ), while others have identified no relationship between obesity and depression ( 12 ).…”

Body Mass Index And Inflammation In Depression And Treatment-Resistant Depression: A Mendelian Randomization Study

“…A meta-analysis reported a positive association only in adults older than 20 years of age but not in children and adolescents [40]. Recent studies derived a binary classification of overweight (metabolically favourable and unfavourable adiposity) based on metabolic sequelae, namely hyperlipidemia, compromise in liver function, and sex hormone levels [58,16]. Whilst individuals with favourable adiposity face much less of the commonly described adverse effects of high adiposity, both phenotypes appeared to exert effects of similar magnitude on the risk of multiple depression outcomes.…”