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  • Diffusion tensor imaging DTI has made it possible to

    2020-07-28

    Diffusion tensor imaging (DTI) has made it possible to investigate microstructural WM abnormalities in vivo (Garin-Muga and Borro, 2014). On the basis of DTI data, several studies reported abnormal WM microstructure in patients with chronic and first-episode psychosis (Andreasen et al., 2011; Bora et al., 2011; Pomarol-Clotet et al., 2010; Tamnes and Agartz, 2016) and even in those who were naïve to antipsychotic drugs (Alvarado-Alanis et al., 2015; Zeng et al., 2016; Zhang et al., 2016). Differential expression levels of myelin-related genes, such as NRG1, ERBB4, DISC1, RTN4R, OLIG2, CNP and MAG, in pentylenetetrazol tissue from subjects with SZ also revealed molecular WM abnormalities, matching the results found by DTI (Roussos and Haroutunian, 2014; Takahashi et al., 2011; Voineskos, 2015). The abnormal expression of myelin-related genes in SZ was most pronounced in the DLPFC, hippocampus, superior temporal cortex and cingulate gyrus (Höistad et al., 2009; Katsel et al., 2005). Only a few reports have demonstrated a relationship among gene variants, WM tract integrity, and cognitive performance. For instance, genetic variability at MAG, OLIG2, and CNP influenced cognitive performance in a manner mediated by the integrity of WM fiber tracts in patients with SZ (Voineskos et al., 2013); more recently, Poletti et al. showed the influence of the COMT Val158Met polymorphism on the association between cognitive function and WM microstructure (Poletti et al., 2016). Our present hypothesis is that SNP variants in the DDR1 locus confer susceptibility to SZ in association with WM microstructure variation and neurocognitive deficits such as processing speed (PS) (Karbasforoushan et al., 2015). To test this hypothesis, we designed 3 different but interrelated studies to achieve three main aims: in Study 1, we aimed to replicate the association between DDR1 variants and SZ; in Study 2, we aimed to determine whether these DDR1 variants influence PS; and in Study 3, we assessed whether there is a link between WM microstructure, PS pentylenetetrazol and DDR1 genotype.
    Materials and methods
    Results
    Discussion
    Conclusions First, we replicated the association of DDR1 with SZ in an independent Spanish sample and demonstrated that a SNP-SNP interaction within DDR1 played a role in the association with the disease. Second, we observed that SZ subjects with the rs2267641CC genotype had decreased PS scores. Third, SZ subjects with the rs1264323AA genotype showed decreased FA in WM regions in association with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.
    Acknowledgements This work was supported by the Spanish ‘Instituto de Salud Carlos III’ from the Ministry of Economy, Industry and Competitivity and FEDER (project grants to [EV] #SAF2007-60086, #PI12/02111 and [JR] # PI14/00292; and contract grants Miguel Servet #CPII16/00018 to [EP-C] and #MS14/00041 to [JR]) and Generalitat de Catalunya Agency ‘AGAUR’ (research grant to [EV] #2017-SGR-444 and to [EP-C] #2017-SGR-1271). Nerea Abasolo was the recipient of a predoctoral fellowship from the Universitat Rovira i Virgili. The Authors have declared that there are no conflicts of interest in relation to the subject of this study.