Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

Pianpian Zhao; Zhimin Ying; Chengda Yuan; Haisheng Zhang; Ao Dong; Jianguo Tao; Xiangjiao Yi; Mengyuan Yang; Wen Jin; Weiliang Tian; David Karasik; Geng Tian; Houfeng Zheng

doi:10.1136/gpsych-2023-101418

Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

Gen Psychiatr. 2024 May 8;37(3):e101418. doi: 10.1136/gpsych-2023-101418. eCollection 2024.

Authors

Pianpian Zhao^{1

2

3

4}, Zhimin Ying⁵, Chengda Yuan⁶, Haisheng Zhang¹, Ao Dong^{1

2

3}, Jianguo Tao^{1

2

3}, Xiangjiao Yi^{1

2

3}, Mengyuan Yang^{1

2

3}, Wen Jin^{1

2

3}, Weiliang Tian⁷, David Karasik⁸, Geng Tian⁹, Houfeng Zheng^{1

2

3

4}

Affiliations

¹ The Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou,Zhejiang, China.
² Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
³ Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
⁴ Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
⁵ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
⁶ Department of Dermatology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China.
⁷ Department of Global Statistics, Eli Lilly and Company, Branchburg, New Jersey, USA.
⁸ Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
⁹ Binzhou Medical University, Yantai, Shandong, China.

Abstract

Background: There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk.

Aims: To explore the relationship between major depressive disorder (MDD) and fracture risk.

Methods: We conducted a nested case-control analysis (32 670 patients with fracture and 397 017 individuals without fracture) and a matched cohort analysis (16 496 patients with MDD and 435 492 individuals without MDD) in the same prospective UK Biobank data set. Further, we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools. We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci. We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study.

Results: We found that MDD was associated with a 14% increase in fracture risk (hazard ratio (HR) 1.14, 95% CI 1.14 to 1.15, p<0.001) in the nested case-control analysis, while fracture was associated with a 72% increase in MDD risk (HR 1.72, 95% CI 1.64 to 1.79, p<0.001) in the matched cohort analysis, suggesting a longitudinal and bidirectional relationship. Further, genetic summary data suggested a genetic overlap between MDD and fracture. Specifically, we identified four shared genomic loci, with the top signal (rs7554101) near SGIP1. The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling. We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa. In addition, we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD.

Conclusions: The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis. The shared genetic components (such as SGIP1) between the diseases suggest that modulating the endocannabinoid system could be a potential therapeutic strategy for both MDD and bone loss.

Keywords: Case-Control Studies; Cohort Studies; Depressive Disorder, Major; Genome-Wide Association Study; Observation.