Molecular Psychiatry (2011) 16, 688–694 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp
LETTERS TO THE EDITOR
Association of white matter integrity with genetic variation in an exonic DISC1 SNP Molecular Psychiatry (2011) 16, 688–689; doi:10.1038/mp.2011.15; published online 1 March 2011
The Disrupted-in-Schizophrenia-1 (DISC1) gene was first identified at the breakpoint of a translocation between chromosomes 1 and 11 that co-segregated with a broad psychiatric phenotype in a large Scottish family,1,2 and subsequent association studies have shown that common genetic variants in DISC1 convey susceptibility to schizophrenia, bipolar disorder and other psychiatric disorders.3 DISC1 is involved in several neurodevelopmental processes, including the development of white matter,4–6 and white matter abnormalities are well-established in schizophrenia and bipolar disorder7 and have a high genetic correlation with susceptibility to both disorders.8,9 Here, we report an association between a common missense variant in DISC1, rs821616 (Ser704Cys), previously associated with schizophrenia,3 and white matter integrity as measured by diffusion tensormagnetic resonance imaging. DNA samples and diffusion tensor-magnetic resonance imaging scans were obtained from 87 healthy individuals between the age of 16 and 25 years. Participants were excluded for major medical or neurological disorders, head injury or learning disability, as well as for personal or family history of psychiatric disorders and history of harmful substance abuse. Genotypes were determined using TaqMan polymerase chain reaction (PCR, TaqMan, AssayByDesign, Applied Biosystems, Foster City, CA, USA). The number of subjects in each genotype group did not significantly deviate from the Hardy–Weinberg equilibrium (TT homozygotes: N = 10, TA heterozygotes: N = 38, AA homozygotes: N = 39, P > 0.99). The genotype groups did not significantly differ with respect to age, sex, intelligence quotient (Wechsler Abbreviated Scale of Intelligence), parental occupation or history of substance abuse (see Supplementary Table 1). Diffusion tensor-magnetic resonance imaging data were acquired using a GE Signa HDx 1.5T (General Electric, Milwaukee, WI, USA) clinical scanner with a single-shot pulsed gradient spin-echo echoplanar imaging sequence, with diffusion gradients (b = 1000s/mm2) applied in 51 non-collinear directions. A total of forty-eight 2.8 mm contiguous axial slices were acquired with a field-of-view of 220 220 mm (repetition time = 17 s, echo time = 93.4 ms and matrix = 96 96, zero-filled to 128 128).
The scans were pre-processed using standard procedures from FSL (http://www.fmrib.ox.ac.uk/fsl), including correction for eddy current-induced distortions and bulk subject motion, brain extraction and calculation of diffusion tensor characteristics, including principal eigenvector orientations and fractional anisotropy (FA) values for all brain voxels. Subsequently, we carried out tract-based spatial statistics in order to minimize registration errors and avoid partial volume effects. Briefly, tract-based spatial statistics is an advanced method of crosssubject white matter registration that projects each subject’s maximum FA-voxels onto a common ‘white matter skeleton’, which is created using the average of all individual’s FA volumes.10 This results in one skeletonized FA volume in standard 1 1 1 mm Montreal Neurological Institute space per subject. To compare the genotype groups with respect to FA, non-parametric voxel-wise T-tests were applied to the skeletons using ‘randomise’ in FSL. Threshold-free cluster enhancement was applied to obtain clusterwise statistics corrected at the whole-brain level (PFWE < 0.05). The A allele was associated with reduced FA, with significant decreases in the A-allele carriers compared with TT (three clusters: K = 33 929; K = 170; K = 46 voxels) and in AA compared with the TT genotype group (ten clusters: K = 21 259; K = 1061; K = 509; K = 381; K = 322; K = 272; K = 118; K = 14; K = 7; K = 6 voxels). These contrasts showed large clusters that spread over most parts of the skeleton (Figure 1; Supplementary Figure 2). A contrast comparing the AA group to T-allele carriers showed four smaller clusters of relative decreases in the AA group (K = 285; K = 77; K = 75; K = 50 voxels; Supplementary Figure 3), mainly located in the right superior longitudinal fasciculus. There were no interactions between rs821616 and sex, neither on the wholeskeleton level nor on the averages extracted from significant voxels within each cluster (Supplementary Figure 4). Here, we show that white matter integrity is associated with genetic variation in an exonic-DISC1 single-nucleotide polymorphism in healthy individuals. DISC1 is known to interact with multiple developmental signaling pathways, including neuronal proliferation and differentiation,4 axon growth4,5 and myelination.6 Notably, knock-down of DISC1 function in zebrafish also leads to severe disruption of axonal development.5 Our results support a similarly important role for DISC1 in white matter
Letters to the Editor
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Figure 1 Results of tract-based spatial statistics comparing rs821616 A carriers to TT homozygotes. Voxels in which fractional anisotropy (FA) was significantly reduced in A carriers compared with TT homozygotes are shown in red–yellow. There were no voxels in which FA was increased in A carriers. For better visibility the tract-based spatial statistics skeleton has been thickened using the ‘tbss_fill’ command in FSL. The images are in radiological convention.
development in humans. Considering DISC1 is one of the main risk loci for psychiatric disorders and white matter integrity is highly heritable, the present data provide a plausible mechanistic link between enhanced genetic risk through inheritance of DISC1 genotypes and the development of psychiatric disorders.
Conflict of interest The authors declare no conflict of interest. E Sprooten1, JE Sussmann1, TW Moorhead1, HC Whalley1, C ffrench-Constant2, HP Blumberg3, ME Bastin4,5, J Hall1, SM Lawrie1 and AM McIntosh1 1 Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK; 2 MRC Centre for Regenerative Medicine, Royal Infirmary, Edinburgh, UK; 3Departments of Psychiatry and Diagnostic Radiology, Yale School of Medicine, New Haven, CT, USA; 4Centre for Clinical Brain Sciences, Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK and 5Medical and Radiological Sciences (Medical Physics), University of Edinburgh, Western General Hospital, Edinburgh, UK E-mail:
[email protected]
References 1 Blackwood DHR, Fordyce A, Walker St MT, Clair DM, Porteous DJ, Muir WJ. Am J Hum Genet 2001; 69: 428–433. 2 Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Hum Mol Genet 2000; 9: 1415–1423. 3 Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR et al. Proc Natl Acad Sci USA 2005; 102: 8627–8632. 4 Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK et al. Cell 2009; 136: 1017–1031. 5 Brandon NJ, Millar JK, Korth C, Sive H, Singh KK, Sawa A. J Neurosci 2009; 29: 12768–12775.
6 Wood JD, Bonath F, Kumar S, Ross CA, Cunliffe VT. Hum Mol Genet 2009; 18: 391–404. 7 Sussmann JE, Lymer GKS, McKirdy J, Moorhead TWJ, Mun˜ozManiega S, Job D et al. Bipolar Disord 2009; 11: 11–18. 8 van der Schot AC, Vonk R, Brans RGH, van Haren NEM, Koolschijn PCMP, Nuboer V et al. Arch Gen Psychiatry 2009; 66: 142–151. 9 Hulshoff Pol HE, Schnak HG, Mandl RCW, Brans RGH, van Haren NEM, Baare´ WFC et al. Neuroimage 2006; 31: 482–488. 10 Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nickols TE, Mackay CE et al. Neuroimage 2006; 31: 1487–1505. Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)
Effect of CRMP3 expression on dystrophic dendrites of hippocampal neurons Molecular Psychiatry (2011) 16, 689–691; doi:10.1038/mp.2011.6; published online 22 February 2011
We have previously shown that deleting CRMP3 gene altered prepulse inhibition of the acoustic startle response,1 impaired long-term potentiation and induced dendritic dystrophy in hippocampus.2 In cultured hippocampal neurons, CRMP3 expression resulted in numerous long-branched dendrites, which were inhibited by its dominant-negative isoform.3 Because the levels of CRMP3 expression in hippocampal neurons correlated with dendrite morphogenesis, it is conceivable that CRMP3 may be a potential therapeutic target in neuronal dystrophy affecting hippocampal dendrites. In this study, we report that CRMP3 overexpression prevents dystrophy of dendrites occurring in a neurotoxic context. Molecular Psychiatry
