Separating the effects of childhood and adult obesity on depression, subjective well-being, and suicide attempt: a Mendelian randomization study.

Abstract

Observational studies have linked obesity, both in childhood and adulthood, with higher risks of depression, reduced subjective well-being (SWB), and suicide attempts (SA). However, the causality remains unclear. This study aimed to investigate the causal effects of childhood and adult obesity on depression, SWB, and SA. A bidirectional two-sample Mendelian randomization (MR) was performed using genome-wide association study (GWAS) data to examine the causal effects of body mass index (BMI) on depression, SWB, and SA. The inverse variance weighted method was used for primary analysis. Univariable and multivariable MR were employed to assess the total and independent effects of early life and adult body size. Cochran's Q test and MR-Egger intercept were applied to evaluate heterogeneity and pleiotropy. Genetically predicted BMI was significantly associated with an increased risk of major depressive disorder (MDD: OR = 1.13, 95%CI = 1.06-1.22, p = 6.1 × 10⁻⁴), SA-ISGC (OR = 1.17, 95%CI = 1.08-1.27, p = 1.9 × 10⁻⁴), and SA-iPSYCH (OR = 1.31, 95%CI = 1.12-1.54, p = 6.2 × 10⁻⁴). No significant causal effects of MDD, SWB, or SA on BMI were found. Early-life body size showed no direct effect on MDD or SA. However, adult body size was directly linked to increased risks of MDD (OR = 1.32, 95%CI = 1.13-1.55, p = 4.7 × 10⁻⁴), SA-ISGC (OR = 1.24, 95%CI = 1.03-1.47, p = 0.022), and SA-iPSYCH (OR = 1.80, 95%CI = 1.29-2.50, p = 5.6 × 10⁻⁴). This study provides robust evidence supporting a causal link between obesity and an increased risk of both depression and SA, with adult body size exerting a more direct impact on these outcomes than early-life body size.