2023-05-19
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) [1] and bipolar disorder (BD) [2], 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 [3] and with decreased processing speed in patients with SCZ [3]. 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.
References
1. PMID: 29483656
2. PMID: 31043756
3. PMID: 30597424
4. PMID: 31108116
5. PMID: 22421314
Analytic Plan
General Hypotheses:
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.
Participants:
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).
Phenotype definition:
Baseline evaluations from the Bipogent and PsyCourse cohorts will be considered:
- Socio-demographics
- 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.
Statistical Analyses:
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.
Resources needed
Socio-Demographics:
v1_sexv1_age
v1_marital_stat
v1_partner
v1_liv_aln
v1_school
v1_prof_dgr
v1_ed_status
v1_curr_paid_empl
v1_disabl_pens
v1_spec_emp
v1_wrk_abs_pst_5_yrs
v1_cur_work_restr
v1_center
Ethnicity:
v1_cntr_brth
Psychiatric Treatment:
v1_outpat_psy_trm
v1_daypat_inpat_trm
v1_age_1st_inpat_trm
v1_dur_illness
v1_age_1st_out_trm
v1_Antidepressants
v1_Antipsychotics
v1_Mood_stabilizers
v1_Tranquilizers
v1_Other_psychiatric
v1_lith
v1_lith_prd
Diagnosis (personal and familiar):
v1_fam_hist
v1_scid_dsm_dx_cat
v1_stat
v1_scid_dsm_dx
v1_scid_age_MDE
v1_scid_no_MDE
v1_scid_age_mania
v1_scid_no_mania
v1_scid_age_hypomania
v1_scid_ever_psyc
Psychiatric symptoms:
v1_ymrs_itm1
v1_ymrs_itm2
v1_ymrs_itm3
v1_ymrs_itm4
v1_ymrs_itm5
v1_ymrs_itm6
v1_ymrs_itm7
v1_ymrs_itm8
v1_ymrs_itm9
v1_ymrs_itm10
v1_ymrs_itm11
v1_ymrs_sum
v1_idsc_itm1
v1_idsc_itm2
v1_idsc_itm3
v1_idsc_itm4
v1_idsc_itm5
v1_idsc_itm6
v1_idsc_itm7
v1_idsc_itm8
v1_idsc_itm9
v1_idsc_itm9a
v1_idsc_itm9b
v1_idsc_itm10
v1_idsc_itm11
v1_idsc_itm12
v1_idsc_itm13
v1_idsc_itm14
v1_idsc_itm15
v1_idsc_itm16
v1_idsc_itm17
v1_idsc_itm18
v1_idsc_itm19
v1_idsc_itm20
v1_idsc_itm21
v1_idsc_itm22
v1_idsc_itm23
v1_idsc_itm24
v1_idsc_itm25
v1_idsc_itm26
v1_idsc_itm27
v1_idsc_itm28
v1_idsc_itm29
v1_idsc_itm30
v1_idsc_sum
v1_panss_p1
v1_panss_p2
v1_panss_p3
v1_panss_p4
v1_panss_p5
v1_panss_p6
v1_panss_p7
v1_panss_sum_pos
v1_panss_n1
v1_panss_n2
v1_panss_n3
v1_panss_n4
v1_panss_n5
v1_panss_n6
v1_panss_n7
v1_panss_sum_neg
v1_panss_g1
v1_panss_g2
v1_panss_g3
v1_panss_g4
v1_panss_g5
v1_panss_g6
v1_panss_g7
v1_panss_g8
v1_panss_g9
v1_panss_g10
v1_panss_g11
v1_panss_g12
v1_panss_g13
v1_panss_g14
v1_panss_g15
v1_panss_g16
v1_panss_sum_gen
v1_panss_sum_tot
Level of functioning:
v1_gaf
Neuropsychological Evaluation:
v1_nrpsy_com
v1_nrpsy_lng
v1_nrpsy_mtv
v1_nrpsy_tmt_A_rt
v1_nrpsy_tmt_A_err
v1_nrpsy_tmt_B_rt
v1_nrpsy_tmt_B_err
v1_nrpsy_dgt_sp_frw
v1_nrpsy_dgt_sp_bck
v1_nrpsy_dg_sym
v1_nrpsy_mwtb
v2_nrpsy_vlmt
v2_nrpsy_vlmt_check
v2_nrpsy_vlmt_corr
v2_nrpsy_vlmt_lss_d
v2_nrpsy_vlmt_lss_t
v2_nrpsy_vlmt_rec
Genetic GSA data (imputed and raw).