Nicholas E Clifton1, Leonardo Collado-Torres2, Emily E Burke3, Antonio F Pardiñas4, Janet C Harwood4, Arianna Di Florio4, James T R Walters4, Michael J Owen5, Michael C O'Donovan4, Daniel R Weinberger6, Peter A Holmans4, Andrew E Jaffe7, Jeremy Hall5. 1. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: cliftonne@cardiff.ac.uk. 2. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland; Centre for Computational Biology, Johns Hopkins University Medical Campus, Baltimore, Maryland. 3. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland. 4. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. 5. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. 6. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland; Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland. 7. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland; Centre for Computational Biology, Johns Hopkins University Medical Campus, Baltimore, Maryland; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Electronic address: andrew.jaffe@libd.org.
Abstract
BACKGROUND: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. METHODS: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. RESULTS: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes. CONCLUSIONS: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
BACKGROUND: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. METHODS: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. RESULTS: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes. CONCLUSIONS: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.