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Recent evidence indicates that DDR1 participates in myelination and that variants of DDR1 are associated with decreased cognitive processing speed (PS) in schizophrenia (SZ). Here, we explored whether DDR1 variants were associated with PS in subjects diagnosed with an early psychosis (EP), a condition often preceding SZ. Data from two Spanish independent samples (from Reus and Santander) including patients with EP (n = 75 and n = 312, respectively) and healthy controls (HCs; n = 57 and n = 160) were analyzed. The Trail Making Test part A was used to evaluate PS. Participants underwent genotyping to identify DDR1 variants rs1264323 and rs2267641. Cross-sectional data were analyzed with general linear models and longitudinal data were analyzed using mixed models. We examined the combined rs1264323AA-rs2267641AC/CC genotypes (an SZ-risk combination) on PS. The SZ-risk combined genotypes were associated with increased PS in EP patients but not in HCs in the cross-sectional analysis. In the longitudinal analysis, the SZ-risk combined genotypes were significantly associated with increased PS in both HCs and EP patients throughout the 10-year follow-up but no genotype × time interaction was observed. These results provide further evidence that DDR1 is involved in cognition and should be replicated with other samples.

DDR1 has been linked to schizophrenia (SZ) and myelination. Here, we tested whether DDR1 variants in people at risk for SZ influence white matter (WM) structural variations and cognitive processing speed (PS). First, following a case-control design (Study 1), SZ patients (N = 1193) and controls (N = 1839) were genotyped for rs1264323 and rs2267641 at DDR1, and the frequencies were compared. We replicated the association between DDR1 and SZ (rs1264323, adjusted P = 0.015). Carriers of the rs1264323AA combined with the rs2267641AC or CC genotype are at risk to develop SZ compared to the other genotype combinations. Second, SZ patients (Study 2, N = 194) underwent an evaluation of PS using the Trail Making Test (TMT) and DDR1 genotyping. To compare PS between DDR1 genotype groups, we conducted an analysis of covariance (including rs1264323 as a covariate) and found that SZ patients with the rs2267641CC genotype had decreased PS compared to patients with the AA and AC genotypes. Third, 54 patients (Study 3) from Study 2 were selected based on rs1264323 genotype to undergo reevaluation, including a DTI-MRI brain scan. To test for associations between PS, WM microstructure and DDR1 genotype, we first localized those WM regions where fractional anisotropy (FA) was correlated with PS and tested whether FA showed differences between the rs1264323 genotypes. SZ patients with the rs1264323AA genotype showed decreased FA in WM regions associated with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor that is activated by fibrillar collagens. Here, we review the expression and role of DDR1 in the central nervous system (CNS). In a murine model, DDR1 is expressed in oligodendrocytes in the developing brain and during remyelination. In human adult brain tissue, DDR1 is detected in a similar pattern as other classical myelin proteins such as myelin basic protein (MBP). Up to 50 transcripts of DDR1 have been detected in human tissues, of which 5 isoforms have been identified. In the human brain, all 5 isoforms are detectable, but DDR1b is the most highly expressed, and DDR1c is coexpressed with myelin genes. DDR1 sequence variants have been associated with psychiatric disorders, and upregulation of this gene occurs in gliomas. Moreover, mutations in DDR1 have been found in tumors of Schwann cells, which are the myelinating cells of the peripheral nervous system. All these data suggest that DDR1 plays a role in myelination and is relevant to neuropsychiatric diseases.

Background: Studies have associated maternal stress during pregnancy with CNS disorders including schizophrenia. In Danish register data we showed that the loss of a close relative during and after pregnancy was associated with offspring schizophrenia risk. It has been speculated that stressful life events enhance production of glucocorticoids that adversely affect neurodevelopment in the immature brain, increasing the risk of mental illness in adolescence or adult life. The authors hypothesized that the effect of bereavement was mediated via cortisol, and in part could be explained by variation in the gene HSD11B2 encoding the glucocorticoid regulating enzyme 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2). Methods: A matched case-control study with 716 schizophrenia cases and 782 controls, matched on sex, exact date of birth, born in Denmark, alive and with no history of schizophrenia on the date of first diagnosis of schizophrenia of the matched case, and also including all their first-degree relatives. We used information from national registers and, to determine whether the effect of bereavement could be explained by variation in HSD11B2. Two single nucleotide polymorphisms (SNPs) from the locus of HSD11B2 were genotyped (rs5479 and 56303414), and one from a neighboring gene (rs9922624), and the data was analyzed with conditional logistic regression. Results: We found a significant protective effect of each of the variant alleles for rs9922624 (odds ratio (OR) 0.60, [95% confidence interval (CI), 0.42-0.88]) and rs5479 (OR 0.55 (95% CI 0.34-0.90). When stress at the age of 3-9 years co-occurred in individuals with the variant allele, we found that the risk of schizophrenia was increased, though not significant. The interaction between stress at the age of 3-9 years and the allele however was significant with (OR 3.02 (95% CI 1.32-6.93) and (OR 3.92 (95% CI 1.46-10.54) for rs9922624 and rs5479 respectively. Discussion: Our results suggest that functional variation in 11βHSD2 might be a predisposing factor for schizophrenia after stress exposure, since we found interaction between the SNPs in the gene and stress. However, maybe due to lack of power, we were not able to show any significant risk of having the allele after stress exposure in regard to schizophrenia.