Causal relationship between neuroticism and bone mineral density: A univariable and multivariable Mendelian randomization study

Recent observational studies have indicated that psychiatric disorders were associated with risk of bone mineral density (BMD) reduction. But the causal relationship between neuroticism and BMD remained unclear. By using public genome-wide association study data, a 2-sample bidirectional Mendelian randomization (MR) study was performed to investigate the causal relationship between neuroticism and BMD (heel BMD, forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD). Inverse-variance weighted, weighted median, and MR-Egger were used to assess the causal effects. Multiple sensitivity analyses were conducted to assess the potential bias of the causal estimates. Multivariable MR analysis was used to assess the direct causal effects of neuroticism on BMD with adjustment of common risk factors of BMD reduction. Univariable MR analysis indicated that genetically predicted higher neuroticism was significantly associated with an increased risk of heel BMD reduction (inverse-variance weighted β = -0.039; se = 0.01; P = .0001; Bonferroni-corrected P = .0005) but not with other BMD (forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD) potentially due to limited statistical power. The causal effects remained significant after accounting for the effects of body mass index, smoking, and drinking. Genetic proxy for higher neuroticism was significantly associated with an increased risk of heel BMD reduction. Further studies were warranted to elucidate the underlying biological mechanisms and explore the potential application in disease early screening and management.