Mendelian Randomization Analysis of the Possible Causal Relationships Between Neurodevelopment-Related Proteins and Bipolar Disorder

Abstract

Background

Bipolar disorder (BD) is a complex mental condition of which the mechanism of onset remains unclear. Mendelian randomization (MR) allows evaluation of the causal effects of biomarkers by minimizing the risks of reverse causation and confounding factors. In this study, MR was used to assess the causal relationships between neurodevelopment-related proteins and BD, thereby providing potential evidence for the neurodevelopmental hypothesis of this mental disorder.

Methods

Leveraging data from large-scale genome-wide association studies (GWASs), the associations between six neurodevelopment-related proteins and BD were analyzed using five MR approaches; namely, inverse-variance weighted, weighted median, MR–Egger, simple mode, and weighted mode methods. The neurodevelopment-related proteins were selected in the study with 5368 European descents. GWAS of BD come from the Psychiatric Genomics Consortium (N_Case = 41,917, N_Control = 371,549).

Results

The analyses identified robust causal relationships between BD and the proteins inter-alpha-trypsin inhibitor heavy chain (ITIH)5 (OR = 1.08, 95% CI = 1.00–1.17, p = 0.04) and neurofascin (NFASC) (OR = 0.96, 95% CI = 0.92–1.00, p = 0.042). Initial findings for ITIH1 and ITIH3 were deemed unreliable due to pleiotropy (ITIH1: MR–Egger intercept p = 0.025) or heterogeneity (ITIH3: Cochran's Q p = 0.001). Furthermore, the MR analyses failed to yield evidence supporting a causal effect of liability to BD on neurodevelopment-related proteins.

Conclusion

The MR analysis indicated potential causal relationships between two neurodevelopment-related proteins (NFASC and ITIH5) and BD. Further studies are required to validate these results and elucidate the specific functions of these proteins in the development of this mental disorder.