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Objective: Recent genomewide association studies have implicated the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) genetic variant in schizophrenia, which is associated with functional brain changes and cognitive deficits in healthy individuals. However, the impact of CACNA1C on brain white matter integrity in schizophrenia remains unclear. On the basis of prior evidence of CACNA1C-mediated changes involving cortical brain regions, we hypothesize that CACNA1C risk variant rs1006737 is associated with reductions of white matter integrity in the frontal, parietal, and temporal regions and cingulate gyrus., Method: A total of 160 Chinese participants (96 DSM-IV-diagnosed patients with schizophrenia and 64 healthy controls) were genotyped by using blood samples and underwent structural magnetic resonance imaging and diffusion tensor imaging scans from 2008 to 2012. Two-way analysis of covariance was employed to examine CACNA1C-related genotype effects, diagnosis effects, and genotype × diagnosis interaction effects on fractional anisotropy (FA) of relevant brain regions., Results: Significant diagnosis-genotype interactions were observed (left frontal lobe mean FA: F₁,₁₅₆ = 6.22, P = .014; left parietal lobe mean FA: F₁,₁₅₆ = 7.14, P = .008; left temporal lobe mean FA: F₁,₁₅₆ = 8.37, P = .004). Compared with patients who were A carriers, patients who were G homozygotes had lower mean FA in the left frontal lobe (F₁,₉₃ = 2.504, P = .014), left parietal lobe (F₁,₉₃ = 2.37, P = .020), and left temporal lobe (F₁,₉₃ = 3.01, P = .003), with standardized effect sizes of -1.43, -1.3, and -1.0, respectively., Conclusions: CACNA1C risk variant rs1006737 affects cortical white matter integrity in schizophrenia. Further imaging genetic investigations on the mediating effect of CACNA1C in schizophrenia can uncover brain circuitries involved in schizophrenia and suggest potential novel targets for intervention., (© Copyright 2014 Physicians Postgraduate Press, Inc.)