Exploring the biological relationships between iron metabolism markers and psychiatric disorders

Iron is an essential element involved in a wide range of biological processes, including development and neurologic function. Perturbations in iron homeostasis can affect neurotransmitter balance since it serves as a cofactor for key enzymes involved in limiting steps of the monoamine biosynthesis pathway. Congruently, disturbances in iron metabolism or biomarkers have been associated with several neuropsychiatric conditions. The aim of this study is to explore the genetic correlation and causality between four iron-related biomarkers (i.e. ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation (TSP)) and major psychiatric disorders (i.e. attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ)). We conducted global and local genetic correlation analyses, using the Linkage Disequilibrium Score Regression (LDSC) and the Local Analysis of [co]Variant Annotation (LAVA) approaches, respectively, applied to the summary statistics from the most recent genome-wide association studies to investigate pleiotropy. We additionally performed Two-Sample Mendelian Randomization (2SMR) using the MR-Base package to explore causal relationships between these traits. Our LDSC analysis revealed a significant and positive correlation between TIBC and MDD. We observed at least one significant local genetic correlation for all psychiatric disorders, except for ASD, predominantly involving TIBC and serum iron biomarkers. Interestingly, two regional partitions of the genome associated with the TIBC-MDD pair presented opposite correlation signs. 2SMR results failed to show causality between any of the iron biomarkers and the psychiatric disorders evaluated; however, some trait pairings exhibited significant heterogeneity and violated MR assumptions, precluding us from robustly inferring a lack of causality. Overall, our findings suggest shared and pleiotropic effects of genetic variants between specific iron biomarkers and psychiatric disorders, which were more evident when partitioning the genome rather than in the global analysis across the genome. TIBC emerged as a relevant biomarker, especially for MDD, although the divergent correlations suggest a complex relationship, potentially involving differential regulation processes that require further investigation. As perspectives of this work, besides exploring in more detail the genomic regions showing significant local genetic correlations, mainly in terms of regulatory processes, additional MR methods and sensitivity analyses should be performed to confirm the lack of causality between the trait pairs evaluated.