Schizophrenia Research Forum - A Catalyst for Creative Thinking

Forum Discussion: How Might Dysbindin Affect the Schizophrenic Brain?


View article

In our Forum Discussion “journal club” series, the editors of Neuropsychopharmacology provide access to the full text of a recent article. An introduction by Monsheel Sodhi, Assistant Professor, Department of Psychiatry and Behavioral Neurobiology, UAB, gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on….

Donohoe G, Frodl T, Morris D, Spoletini I, Cannon DM, Cherubini A, Caltagirone C, Bossù P, McDonald C, Gill M, Corvin AP, Spalletta G. Reduced Occipital and Prefrontal Brain Volumes in Dysbindin-Associated Schizophrenia. Neuropsychopharmacology. 2009 Sep 30. [Epub ahead of print]. Abstract

Our thanks to Nature Journals for allowing this article to be posted for discussion at SRF.

View Comments By:
Marquis Vawter — Posted 15 December 2009
Gary Donohoe — Posted 17 December 2009
Joel Kleinman — Posted 13 February 2010


Background Text
By Monsheel Sodhi, Assistant Professor, Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham

This paper reports new data that may increase interest in the move toward using genetic markers to predict more focused phenotypes in schizophrenia. The heritability of morphological changes in the brains of schizophrenia patients has been found to be high (Peper et al., 2007). Therefore, the authors of the current paper have investigated one of the candidate genes for schizophrenia identified by positional cloning, the gene encoding dystrobrevin-binding protein 1 (dysbindin).

There have been many case-control studies published that have produced conflicting data on the genetic association between dysbindin and schizophrenia; for example, at least 19 studies have been positive (see www.SZgene.org). However, in the current paper, the authors show that the gene encoding dysbindin is associated with altered brain morphology, as measured by voxel-based morphometry. Subjects carrying a risk haplotype comprising the dysbindin SNPs P1655 (rs2619539), P1635 (rs3213207), and SNP66961 (rs2619538) (abbreviated to C-A-T) have reductions in gray matter volumes of the right dorsolateral prefrontal cortex and left occipital cortex.

The same risk haplotype may be a marker in a subset of the schizophrenia population who have a specific combination of symptoms due to particular structural and/or developmental defects in the brain. These morphological changes could explain certain symptoms exhibited by patients, particularly cognitive and negative ones, which have previously been associated with the C-A-T haplotype of dysbindin (Corvin et al., 2008).

Dysbindin is expressed in forebrain glutamate neurons. It interacts with proteins involved in the presynaptic trafficking of vesicles and exocytosis. In fact, mice with a null mutation of the dysbindin gene have been reported to show impaired spatial working memory relative to wild-type controls (Jentsch et al., 2009).

Taken together, these data indicate that dysbindin impacts brain functions such as working memory. This may be due to impaired brain development via dysregulation of presynaptic glutamatergic transmission. Therefore, functional genetic variation of dysbindin could contribute to some of the more devastating symptoms experienced by patients with schizophrenia.

If these findings are replicated, many questions will need to be addressed. For instance, by what mechanism(s) could dysbindin change gray matter volume in these brain regions? Could patients who have schizophrenia and abnormal gray matter volume in these specific regions have a subtype of schizophrenia that is attributable to altered dysbindin?

References:
Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp. 2007;28(6):464-73. Abstract

Corvin A, Donohoe G, Nangle JM, Schwaiger S, Morris D, Gill M. A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis. Neurosci Lett. 2008;431(2):146-9. Abstract

Jentsch JD, Trantham-Davidson H, Jairi C, Tinsley M, Cannon TD, Lavin A. Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology. 2009 July 29. Abstract

Comments on Online Discussion
Comment by:  Marquis Vawter
Submitted 15 December 2009
Posted 15 December 2009

The article by Donohoe et al. asks several questions about the risk architecture of schizophrenia. Will some of the genetic risk factors have specific effects on brain volume and cognition, while others contribute to specific negative, positive, and other symptoms? It will be of interest to the field of cognition, genetics, and neuroimaging to look across domains represented by this work and by many others that preceded it. Will certain “subtypes” or dimensions of schizophrenia be more robustly associated with dysbindin haplotypes? Future work could address research-based, diagnostic criteria for schizophrenia that will ultimately be useful for finding additional intermediate phenotypes beyond specific brain volume and cognitive deficits associated with dysbindin. The paper further suggests that study of this haplotype and others will be useful also in controls for determining the genetic effect of this locus on cognition and brain size.

View all comments by Marquis VawterComment by:  Gary Donohoe
Submitted 17 December 2009
Posted 17 December 2009

Interest in dysbindin as a candidate gene for schizophrenia has persisted despite the new wave of risk variants identified in genomewide association studies. The year 2009 was particularly important in advancing current understanding of the biological relevance of this gene for schizophrenia risk, both through animal studies and through human imaging studies. Our paper (Donohoe et al., 2010) represents just one of six magnetic resonance imaging studies of dysbindin published in the past year (Mechelli et al., 2010; Markov et al., 2009a; Markov et al., 2009b; Thimm et al., 2009; Narr et al., 2009; Dutt et al., 2009), five of which report statistical evidence association between dysbindin variants and changes in either brain structure or function. Given the ambivalence felt by some psychiatric genetics researchers about imaging genetics on account of the associated multiple testing burden, it is important to note what level of consistency exists among these studies.

Our study was based on the C-A-T risk haplotype (consisting of rs2619539, rs3213207, and rs2619538) first identified by Williams et al. (2004). The only other study to report on an overlapping variant was Mechelli et al. (2010), which focused on rs2619538. This study used functional MRI to investigate visual processing in 61 healthy 10- to 12-year-olds, and found significant differences in lingual, fusiform, and inferior occipital cortex, the last of which was also implicated in our structural study. The remaining four studies by Narr et al. (2009), Thimm et al. (2009), and Markov et al. (2009a; 2009b) all focused on the risk variant rs1018381 identified by Straub et al. (2002). This variant was found to be associated with several cortical regions including the prefrontal cortex (particularly the middle and inferior frontal gyri) and the superior and middle temporal gyrus. Of these, the reported prefrontal associations overlapped significantly with our findings. The only other structural imaging study, by Narr et al. (2009), reported cortical thinning in patients, particularly in the temporal lobes, but also some evidence of cortical thickening in healthy controls in the same regions. The one negative study by Dutt et al. (2009) investigated both rs1018381 and rs1011313, as well as a number of other variants at other gene loci; despite a large sample size they failed to identify any significant associations at any loci.

One challenge for interpreting the findings of these structural and functional studies is to understand how 1) the neuropsychological deficits previously reported in patients, 2) the reduced volume reported in our study, and 3) the cortical thinning in patients reported in Narr et al. (2009) might be correlated with the evidence of increased cortical activity in the fMRI studies described above. Both Markov et al. (2009b) and Thimm et al. (2009) suggest that increased activity associated with the dysbindin risk variant may represent reduced cortical efficiency in the associated brain regions of risk carriers. Whether this inefficiency may relate to the structural changes observed in our study is unclear. Future studies in which both structural and functional data are available can hopefully clarify this point. What is clear is that the dysbindin risk variants reported here are associated with structural and functional changes throughout the brain in a replicable manner and suggest one way in which increased risk may be conferred in patients carriers.

References:

Donohoe G, Frodl T, Morris D, Spoletini I, Cannon DM, Cherubini A, Caltagirone C, Bossù P, McDonald C, Gill M, Corvin AP, Spalletta G. Reduced Occipital and Prefrontal Brain Volumes in Dysbindin-Associated Schizophrenia. Neuropsychopharmacology. 2010 Sep 30. Abstract

Dutt A, McDonald C, Dempster E, Prata D, Shaikh M, Williams I, Schulze K, Marshall N, Walshe M, Allin M, Collier D, Murray R, Bramon E. The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis. Psychol Med. 2009 Nov;39(11):1783-97. Abstract

Narr KL, Szeszko PR, Lencz T, Woods RP, Hamilton LS, Phillips O, Robinson D, Burdick KE, DeRosse P, Kucherlapati R, Thompson PM, Toga AW, Malhotra AK, Bilder RM. DTNBP1 is associated with imaging phenotypes in schizophrenia. Hum Brain Mapp. 2009 Nov;30(11):3783-94. Abstract

Markov V, Krug A, Krach S, Jansen A, Eggermann T, Zerres K, Stöcker T, Shah NJ, Nöthen MM, Treutlein J, Rietschel M, Kircher T. Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals. Hum Brain Mapp. 2009a Jul 31. Abstract

Markov V, Krug A, Krach S, Whitney C, Eggermann T, Zerres K, Stöcker T, Shah NJ, Nöthen MM, Treutlein J, Rietschel M, Kircher T. Genetic variation in schizophrenia-risk-gene dysbindin 1 modulates brain activation in anterior cingulate cortex and right temporal gyrus during language production in healthy individuals. Neuroimage. 2009b Oct 1;47(4):2016-22. Abstract

Mechelli A, Viding E, Kumar A, Pettersson-Yeo W, Fusar-Poli P, Tognin S, O'Donovan MC, McGuire P. Dysbindin modulates brain function during visual processing in children. Neuroimage. 2010 Jan 1;49(1):817-22. Abstract

Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, Cesare AJ, Gibberman A, Wang X, O'Neill FA, Walsh D, Kendler KS. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet. 2002 Aug;71(2):337-48. Abstract

Thimm M, Krug A, Markov V, Krach S, Jansen A, Zerres K, Eggermann T, Stöcker T, Shah NJ, Nöthen MM, Rietschel M, Kircher T. The impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval. Hum Brain Mapp. 2009 Jul 20. Abstract

Williams NM, Preece A, Morris DW, Spurlock G, Bray NJ, Stephens M, Norton N,Williams H, Clement M, Dwyer S, Curran C, Wilkinson J, Moskvina V, Waddington JL, Gill M, Corvin AP, Zammit S, Kirov G, Owen MJ, O'Donovan MC. Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1). Arch Gen Psychiatry. 2004 Apr;61(4):336-44. Abstract

View all comments by Gary DonohoeComment by:  Joel Kleinman
Submitted 13 February 2010
Posted 13 February 2010

The Donohoe et al. Neuropsychopharmacology paper is an excellent study of the association of a dysbindin risk-associated haplotype with brain structure and function, which are intermediate phenotypes for schizophrenia. Determining the mechanisms by which dysbindin effects brain development may also elucidate why risk-associated haplotypes are associated with brain structure, cognition, and risk for disease.

View all comments by Joel Kleinman