Unraveling shared susceptibility loci and Mendelian genetic associations linking educational attainment with multiple neuropsychiatric disorders

Dongze Chen; Yi Zhou; Yali Zhang; Huatang Zeng; Liqun Wu; Yuyang Liu

doi:10.3389/fpsyt.2023.1303430

Unraveling shared susceptibility loci and Mendelian genetic associations linking educational attainment with multiple neuropsychiatric disorders

Front Psychiatry. 2024 Jan 4:14:1303430. doi: 10.3389/fpsyt.2023.1303430. eCollection 2023.

Authors

Dongze Chen^#¹, Yi Zhou^#², Yali Zhang³, Huatang Zeng², Liqun Wu², Yuyang Liu²

Affiliations

¹ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genetics, Peking University Cancer Hospital & Institute, Beijing, China.
² Shenzhen Health Development Research and Data Management Center, Shenzhen, China.
³ Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, China.

^# Contributed equally.

Abstract

Background: Empirical studies have demonstrated that educational attainment (EA) is associated with neuropsychiatric disorders (NPDs), suggesting a shared etiological basis between them. However, little is known about the shared genetic mechanisms and causality behind such associations.

Methods: This study explored the shared genetic basis and causal relationships between EA and NPDs using the high-definition likelihood (HDL) method, cross phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) with summary-level data for EA (N = 293,723) and NPDs (N range = 9,725 to 455,258).

Results: Significant genetic correlations between EA and 12 NPDs (r_g range - 0.49 to 0.35; all p < 3.85 × 10^-3) were observed. CPASSOC identified 37 independent loci shared between EA and NPDs, one of which was novel (rs71351952, mapped gene: ARFGEF2). Functional analyses and TWAS found shared genes were enriched in brain tissue, especially in the cerebellum and highlighted the regulatory role of neuronal signaling, purine nucleotide metabolic process, and cAMP-mediated signaling pathways. CPASSOC and TWAS supported the role of three regions of 6q16.1, 3p21.31, and 17q21.31 might account for the shared causes between EA and NPDs. MR confirmed higher genetically predicted EA lower the risk of ADHD (OR_IVW: 0.50; 95% CI: 0.39 to 0.63) and genetically predicted ADHD decreased the risk of EA (Causal effect: -2.8 months; 95% CI: -3.9 to -1.8).

Conclusion: These findings provided evidence of shared genetics and causation between EA and NPDs, advanced our understanding of EA, and implicated potential biological pathways that might underlie both EA and NPDs.

Keywords: Mendelian randomization; educational attainment; genetic correlation; neuropsychiatric disorders; shared genetic architecture.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Sanming Project of Medicine in Shenzhen [No. SZSM202111001].