Discoidin domain receptor 1 gene variants are associated with decreased white matter fractional anisotropy and decreased processing speed in schizophrenia

• Published in: Journal of psychiatric research Vol. 110; pp. 74 - 82
• Main Authors: Gas, Cinta, Canales-Rodríguez, Erick Jorge, Radua, Joaquim, Abasolo, Nerea, Cortés, Maria José, Salvadó, Ester, Muntané, Gerard, Alemán-Gómez, Yasser, Julià, Toni, Marsal, Sara, Sanjuan, Julio, Guitart, Miriam, Costas, Javier, Martorell, Lourdes, Pomarol-Clotet, Edith, Vilella, Elisabet
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2019
• Subjects: Adult; Case-Control Studies; Cognition; Cognitive Dysfunction - physiopathology; DDR1; Discoidin Domain Receptor 1 - genetics; Female; Genetics; Humans; Imaging; Magnetic Resonance Imaging; Male; Middle Aged; Myelin; Polymorphism, Single Nucleotide; Schizophrenia - genetics; Schizophrenia - pathology; Schizophrenia - physiopathology; Spain; White Matter - diagnostic imaging; White Matter - pathology; Spain; DDR1; Genetics; Cognition; Myelin; Imaging
• ISSN: 0022-3956; 1879-1379; 1879-1379
• DOI: 10.1016/j.jpsychires.2018.12.021

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. [Display omitted] •We replicated the association between DDR1 SNP variants and schizophrenia (SZ) in a larger Spanish sample.•An interaction between rs1264323 and the functional rs2267641 is associated with SZ.•We found an association between the functional SNP rs2267641 and processing speed (PS) in SZ subjects.•SZ subjects with rs1264323AA genotype showed decreased fractional anisotropy in white matter regions with decreased PS.