074_ Role of discoidin domain receptor 1 (DDR1) and other cell cycle genes in the neurocognitive performance of patients with schizophrenia and with bipolar disorder
Research Question and Aims
Discoidin domain receptor 1 (DDR1) is a pleiotropic membrane-anchored tyrosine kinase receptor expressed in multiple tissues, including brain. Genome-wide association studies have found statistically significant associations between variants in the DDR1 locus and the diagnosis of schizophrenia (SCZ)  and bipolar disorder (BD) , however, the mechanism underlying the association between DDR1 and these psychiatric disorders is still unknown. In the past, we demonstrated that SNPs in the DDR1 locus, were associated with SCZ  and with decreased processing speed in patients with SCZ . Recently, we observed that the same SNPs are also associated with the diagnosis of BD and with neurocognitive performance (including processing speed) in patients with BD (manuscript under preparation), suggesting that they could be a genetic marker for these two psychiatric disorders.
The association of SNPs in the DDR1 locus with SCZ and BD may indicate a functional effect regulating differential isoform expression [4,5]. Thus, to further study the involvement of DDR1 isoforms in SCZ and BD, we studied the pattern of expression of DDR1 transcripts in DLPFC of patients with SCZ, patients with BD and healthy controls. We observed that patients with SCZ and patients with BD showed a downregulation of transcripts of the DDR1a and DDR1d isoforms as well as an upregulation of the DDR1c isoform with respect to healthy controls. Also, we observed that the DDR1a transcripts downregulated in disease highly correlated with genes involved in the cell cycle of astrocytes and oligodendrocyte precursor cells (OPCs) and that the whole coexpression module was associated with the diagnosis of SCZ and BD (manuscript submitted). These results suggest that DDR1 expression might be altered in SCZ and BD arresting the proliferation of astrocyte precursors and OPCs.
1. PMID: 29483656
2. PMID: 31043756
3. PMID: 30597424
4. PMID: 31108116
5. PMID: 22421314
The associations between DDR1 SNP variants and the diagnosis and neurocognitive performance of patients with SCZ and patients with BD will be replicated. Cell cycle and brain cell type PRSs calculated from the latest genome-wide association studies (GWAS) in SCZ and BD will be associated with the diagnosis and the performance of patients with SCZ and patients with BD in some domains of neurocognition. Individual genetic variants of cell cycle genes, other than DDR1, will be also associated with the diagnosis and the performance of patients with SCZ and patients with BD in some domains of neurocognition.
For this purpose, we will use cross-sectional data derived from two different cohorts:
1. The Bipogent Cohort: Sociodemographic, clinical (YOUNG, HDRS, FAST, Columbia), neurocognitive (complete battery) and genomic data from 224 controls and 178 patients with BD.
2. The PsyCourse Cohort: Sociodemographic, clinical, neurocognitive and genomic data of patients with schizophrenia, patients with bipolar disorder and controls 1320 clinical and 466 control participants (baseline evaluations).
Baseline evaluations from the Bipogent and PsyCourse cohorts will be considered:
- Psychiatric and medical history
- Medication data
- Family history of psychiatric disease
- Clinical evaluations: mood assessment (HDRS, IDS, YMRS) and functioning (FAST, GAF).
- Neurocognitive assessment: Processing Speed (TMT-A total time/WAIS-III Digit-Symbol coding); attention and working memory (WAIS-III digit span); executive functions (TMT-B); verbal memory (CVLT/VLMT), IQ (WAIS-III, MWT-B).
Polygenic Risk Scores:
Polygenic risk scores (PRS) for major psychiatric disorders (BD, SCZ) will be constructed based on the summary statistics of cell-cycle genes of the latest GWAS for these disorders. PRS-CS tool will be used to infer posterior SNP effect sizes under continuous shrinkage priors and estimate the global shrinkage parameter (φ) using a fully Bayesian approach. PRS will be then calculated in PLINK 1.9 using dosage data independently in the two cohorts, and data will be meta-analyzed.
Logistic and linear regression analyses will be used to study (1) the association between SNPs in the DDR1 locus and the diagnosis and neurocognitive performance of patients with SCZ and BD, (2) the association between variants in the locus of the cell cycle genes and the diagnosis and neurocognitive performance of patients with SCZ and BD, and (3) the association between cell cycle and cell type PRSs and the diagnosis and neurocognitive performance of patients with SCZ and BD. Analyses will be performed in the R software.
Diagnosis (personal and familiar):
Level of functioning:
Genetic GSA data (imputed and raw).