Zinc Finger Gene Points to Schizophrenia Subtype With Spared Cognition
29 July 2010. A clue to the possible role of the ZNF804A gene in psychotic disorders comes from a new study in the July Archives of General Psychiatry. Gary Donohoe of Trinity College in Dublin, Ireland, and colleagues found evidence that the risk variant found in genomewide association studies of psychosis, rather surprisingly, is associated with better performance on certain working and episodic memory tasks in schizophrenia, and thus could define a group of people whose cognition remains relatively intact despite their other symptoms. This group, the authors speculate, may comprise a genetically unique type of schizophrenia that arises through a distinct pathway—a notion that, if backed by future studies, may affect psychiatric research, diagnosis, and treatment.
The single-nucleotide polymorphism (SNP) rs1344706, located in an intron of the zinc finger protein 804A (ZNF804A) gene, came within a hair of being the first to cross the statistical significance finish line in the genomewide association sweepstakes, and a combined psychosis sample that included bipolar cases nudged it into genomewide significance (see SRF related news story). Further genomewide association and other studies have supported the link between rs1344706 and schizophrenia and bipolar disorder in independent samples (see SRF related news story; Zhang et al., 2010; and SZGene entry).
The gene and its protein product remain rather mysterious. Beyond the observation that the eponymous zinc finger domain suggests the protein binds DNA and thus might regulate genes, there are data to show that a putative mouse homolog is expressed in brain. Interestingly, a new study indicates that this mouse homolog is regulated by the Hoxc8 protein (Chung et al., 2010). Hox genes are generally known for their dominant roles in embryonic patterning early in development, but there is also evidence for their role in the adult brain, and even in behavioral disturbances in a possible animal model of obsessive-compulsive behavior (see SRF related news story).
The wider lens of brain activation
The current finding supports the notion that variation in ZNF804A may affect schizophrenia through patterns of brain activation. In a previous magnetic resonance imaging study of healthy subjects performing a cognitive task, Meyer-Lindenberg's group, at the University of Heidelberg in Germany, tied the risk variant to altered connectivity within and between the dorsolateral prefrontal cortex and the hippocampus, areas thought to act up in schizophrenia (see SRF related news story). While that study found no association between the SNP and task performance, a later one from the same group tied the variant not only to changes in brain activation, but also to impaired social cognition in healthy subjects (Walter et al., 2010).
Such findings caused the international team, led by first author James Walters, Cardiff University, Cardiff, Wales, to think that rs1344706 might be associated with cognitive performance in schizophrenia. They considered cognition a possible schizophrenia endophenotype, in part because a variety of cognitive deficits play a key role in the disorder (Bowie and Harvey, 2005). Performance on neuropsychological tests may relate more closely than diagnosis to pathogenesis and, hence, may offer a better window into how the illness develops.
Walters and colleagues examined the possible relationship between the genotype and cognition in patients with schizophrenia and healthy subjects in two stages. The discovery stage involved genotyping an Irish sample for rs1344706 and asking subjects to complete standard tests of cognitive function to obtain measures of IQ, working memory, episodic memory, and attention. The researchers then used analysis of variance to determine whether the SNP was associated with cognitive performance. The second stage entailed using the same methods to try to replicate, in an independent sample of German subjects, any significant associations found in stage one.
The Irish cohort consisted of 297 patients who met DSM-IV criteria for schizophrenia and 165 healthy controls. The German replication sample included 251 patients with schizophrenia, all of whom had experienced symptoms for at least six months, and 1,472 healthy controls who had been randomly selected from the community. Subjects ranged from 18 to 65 years old.
A surprise finding
Not surprisingly, each cognitive indicator—IQ, episodic memory, working memory, and attention—showed that patients had worse cognitive functioning than controls. Less expected were the findings regarding the association between the zinc finger genotype and cognitive deficits. Since the work by Meyer-Lindenberg's group had tied the A (risk) allele at rs1344706 to abnormal brain activation in areas involved in memory and to psychosis, which often comes with cognitive deficits, it stood to reason that carriers of the risk genotype should perform worse than non-carriers on cognitive tests. However, in a counterintuitive twist, carriers of the risk genotype actually performed better than non-carriers.
The study tested two main kinds of memory: working memory and episodic memory. The working memory tasks assessed both verbal and spatial working memory. In the Irish cohort, the ZNF804A genotype interacted with case-versus-control status to predict variance in both kinds of working memory. Analyses limited to control subjects, in which the genotype was only weakly related to performance, suggested that the interaction resulted mainly from the genotype’s effect in patients.
In patients, the genotype explained 2.8 percent of the variance in verbal working memory and 4.4 percent in spatial working memory. Post-hoc tests limited to patients revealed better working memory in AA homozygotes than in CC homozygotes.
The study examined two kinds of episodic memory: immediate and delayed logical memory. For immediate logical memory, genotype interacted with subject group, again reflecting an association in patients that explained almost 3 percent of the variance in performance. Post-hoc tests showed that homozygous and heterozygous risk allele carriers performed better than homozygous subjects who lacked the allele. Analyses also found a significant, but weaker, interaction for delayed episodic memory.
Turning to the German cohort, the researchers were able to replicate the significant associations found in the Irish sample. Again, genotype and case-versus-control status interacted to explain variance in scores for all of the memory tests, a finding driven by the gene’s effects in patients only. For each kind of memory, patients with the AA genotype performed best. In the German patients, genotype explained about 3 percent of the variance in spatial working memory, verbal working memory, and immediate and delayed episodic memory.
While research results seldom replicate as cleanly as they did in this study, finding less impaired cognition in carriers of an allele associated with psychosis defied expectations. In search of an explanation, Walters and colleagues hypothesized that the zinc finger gene variant might be defining a subgroup of patients with schizophrenia whose cognition had been relatively unscathed. If so, they thought, the association should be greatest in analyses restricted to subjects with higher cognitive ability. Sure enough, as IQ rose, the association between the genotype and schizophrenia grew stronger. Similar results emerged when the researchers used memory performance instead of IQ to select the highest-ability groups.
In trying to make sense of the findings, Walters and colleagues considered the possibility that they might result from spurious influences. Statistically, they were able to rule out potential confounding variables, including sociodemographic characteristics, medication, and severity of clinical symptoms. They further reasoned that the gene must not encode for cognition in general, because otherwise it would have affected performance in healthy subjects and, besides, the greatest association with schizophrenia appeared in subjects with relatively high cognitive ability. Rather, the researchers interpreted their findings as evidence that ZNF804A may contribute to a distinct kind of psychosis that develops through a different pathway than other kinds of schizophrenia that bring on greater cognitive impairment. If true, this finding could affect the usefulness of cognition as a general endophenotype for the heterogeneous disorder called schizophrenia.
Taking the results one step further, the researchers speculate that the increased connectivity between the hippocampus and the dorsolateral prefrontal cortex found in previous research “could represent a neural mechanism that spares episodic and working memory in patients by allowing processing of memory information in both structures.” Healthy subjects would not need this compensatory mechanism; therefore, only patients would benefit from it.
Finally, these findings could have implications for the classification of psychotic disorders in general and schizophrenia in particular. Taking a cue from other complex genetic diseases—such as breast cancer, in which the presence of the HER2 gene shapes research and treatment—Walters and colleagues state that their findings support subtyping patients with schizophrenia to clarify underlying molecular and biological pathways. They hint that the psychosis subtype defined by the zinc finger variant may cross diagnostic boundaries to include bipolar disorder. They write, “If confirmed, defining the molecular etiology involved in this group may have important diagnostic, prognostic, and therapeutic implications.”—Victoria L. Wilcox and Hakon Heimer.
Walters JT, Corvin A, Owen MJ, Williams H, Dragovic M, Quinn EM, Judge R, Smith DJ, Norton N, Giegling I, Hartmann AM, Möller HJ, Muglia P, Moskvina V, Dwyer S, O'Donoghue T, Morar B, Cooper M, Chandler D, Jablensky A, Gill M, Kaladjieva L, Morris DW, O'Donovan MC, Rujescu D, Donohoe G. Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia. Arch Gen Psychiatry. 2010 Jul;67(7):692-700. Abstract
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Related News: More Evidence for CNVs in Schizophrenia Etiology—Jury Still Out on Practical ImplicationsComment by: Christopher Ross
, Russell L. Margolis
Submitted 1 August 2008
Posted 1 August 2008
The two recent papers in Nature, from the Icelandic group (Stefansson et al., 2008), and the International Schizophrenia Consortium (2008) led by Pamela Sklar, represent a landmark in psychiatric genetics. For the first time two large studies have yielded highly significant consistent results using multiple population samples. Furthermore, they arrived at these results using quite different methods. The Icelandic group used transmission screening and focused on de novo events, using the Illumina platform in both a discovery population and a replication population. By contrast, the ISC study was a large population-based case-control study using the Affymetrix platform, which did not specifically search for de novo events.
Both identified the same two regions on chromosome 1 and chromosome 15, as well as replicating the previously well studied VCFS region on chromosome 22. Thus, we now have three copy number variants which are replicated and consistent across studies. This provides data on rare highly penetrant variants complementary to the family based study of DISC1 (Porteous et al., 2006), in which the chromosomal translocation clearly segregates with disease, but in only one family. In addition, they are in general congruent with three other studies (Walsh et al., 2008; Kirov et al., 2008; Xu et al., 2008) which also demonstrate a role for copy number variation in schizophrenia. These studies together should put to rest many of the arguments about the value of genetics in psychiatry, so that future studies can now begin from a firmer base.
However, these studies also raise at least as many questions as they answer. One is the role of copy number variation in schizophrenia in the general population. The number of cases accounted for by the deletions on chromosome 1 and 15 in the ISC and Icelandic studies is extremely small--on the order of 1% or less. The extent to which copy number variation, including very rare or even private de novo variants, will account for the genetic risk for schizophrenia in the general population is still unknown. The ISC study indicated that there is a higher overall load of copy number variations in schizophrenia, broadly consistent with Walsh et al and Xu et al but backed up by a much larger sample size, allowing the results to achieve high statistical significance. The implications of these findings are still undeveloped,
Another issue is the relationship to the phenotype of schizophrenia in the general population. Many more genotype-phenotype studies will need to be done. It will be important to determine whether there is a higher rate of mental retardation in the schizophrenia in these studies than in other populations.
Another question is the relationship between these copy number variations (and other rare events) and the more common variants accounting for smaller increases in risk, as in the recent O’Donovan et al. (2008) association study in Nature Genetics. It is far too early to know, but there may well be some combination of rare mutations plus risk alleles that account for cases in the general population. This would then be highly reminiscent of Alzheimer’s disease, Parkinson’s disease, and other diseases which have been studied for a longer period of time.
For instance, in Alzheimer’s disease there are rare mutations in APP and presenilin, as well as copy number variation in APP, with duplications causing the accelerated Alzheimer’s disease seen in Down syndrome. These appear to interact with the risk allele in APOE, and possibly other risk alleles, and are part of a pathogenic pathway (Tanzi and Bertram, 2005). Similarly in Parkinson’s disease, rare mutations in α-synuclein, LRRK2 and other genes can be causative of PD, though notably the G2019S mutation in LRRK2 has incomplete penetrance. In addition, duplications or triplications of α-synuclein can cause familial PD, and altered expression due to promoter variants may contribute to risk. By contrast, deletions in Parkin cause an early onset Parkinsonian syndrome (Hardy et al., 2006). Finally, much of PD may be due to genetic risk factors or environmental causes that have not yet been identified. Further studies will likely lead to the elucidation of pathogenic pathways. These diseases can provide a paradigm for the study of schizophrenia and other psychiatric diseases. One difference is that the copy number variations in the neurodegenerative diseases are often increases in copies (as in APP and α-synuclein), consistent with gain of function mechanisms, while the schizophrenia associations were predominantly with deletions, suggesting loss of function mechanisms. The hope is that as genes are identified, they can be linked together in pathways, leading to understanding of the neurobiology of schizophrenia (Ross et al., 2006).
The key unanswered questions, of course, are what genes or other functional domains are deleted at the chromosome 1, 15, and 22 loci, whether the deletions at these loci are sufficient in themselves to cause schizophrenia, and, if sufficient, the extent to which the deletions are penetrant. Both of the current studies identified deletions large enough to include several genes. The hope is that at least a subset of copy number variations (unlike SNP associations identified in schizophrenia to date) may be causative, making the identification of the relevant genes or other functional domains—at least in principle—more feasible.
Another tantalizing observation is that the copy number variations associated with schizophrenia were defined by flanking repeat regions. This raises the question of the extent to which undetected smaller insertions, deletions or other copy number variations related to other repetitive motifs, such as long tandem repeats, may also be associated with schizophrenia. Identification and testing of these loci may prove a fruitful approach to finding additional genetic risk factors for schizophrenia.
Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A. Genetics of Parkinson's disease and parkinsonism. Ann Neurol. 2006 Oct;60(4):389-98. Abstract
Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O'Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet . 2008 Feb 1 ; 17(3):458-65. Abstract
Porteous DJ, Thomson P, Brandon NJ, Millar JK. The genetics and biology of DISC1—an emerging role in psychosis and cognition. Biol Psychiatry. 2006 Jul 15;60(2):123-31. Abstract
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006 Oct 5;52(1):139-53. Abstract
Singleton A, Myers A, Hardy J. The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R123-6. Abstract
Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell. 2005 Feb 25;120(4):545-55. Abstract
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008 Apr 25;320(5875):539-43. Abstract
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008 Jul;40(7):880-5. Abstract
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Related News: More Evidence for CNVs in Schizophrenia Etiology—Jury Still Out on Practical Implications
Comment by: Daniel Weinberger, SRF Advisor
Submitted 3 August 2008
Posted 3 August 2008
Several recent reports have suggested that rare CNVs may be highly penetrant genetic factors in the pathogenesis of schizophrenia, perhaps even singular etiologic events in those cases of schizophrenia who have them. This is potentially of enormous importance, as the definitive identification of such a “causative” factor may be a major step in unraveling the biologic mystery of the condition. I would stress several issues that need to be considered in putting these recent findings into a broader perspective.
It is very difficult to attribute illness to a private CNV, i.e., one found only in a single individual. This point has been potently illustrated by a study of clinically discordant MZ twins who share CNVs (Bruder et al., AJHG, 2008). Inherited CNVs, such as those that made up almost all of the CNVs described in the childhood onset cases of the study by Walsh et al. (Science, 2008), are by definition not highly penetrant (since they are inherited from unaffected parents). The finding by Xu et al. (Nat Gen, 2008) that de novo (i.e., non-inherited) CNVs are much more likely to be associated with cases lacking a family history is provocative but difficult to interpret as no data are given about the size of the families having a family history and those not having such a history. Unless these family samples are of comparable size and obtained by a comparable ascertainment strategy, it is hard to know how conclusive the finding is. Indeed, in the study of Walsh et al., rare CNVs were just as likely to be found in patients with a positive family history. Finally, in contrast to private CNVs, recurrent (but still rare) CNVs, such as those identified on 1q and 15q in the studies of the International Schizophrenia Consortium (Nature, 2008) and Stefansson et al. (Nature, 2008), are strongly implicated as being associated with the diagnosis of schizophrenia and therefore likely involved in the causation of the illnesses in the cases having these CNVs. In all, these new CNV regions, combined with the VCFS region on 22q, suggest that approximately five to 10 patients out of 1,000 who carry the diagnosis of schizophrenia may have a well-defined genetic lesion (i.e., a substantial deletion or duplication).
The overarching question now is how relevant these findings are to the other 99 percent of individuals with this diagnosis who do not have these recurrent CNVs. Before we had the capability to perform high-density DNA hybridization and SNP array analyses, chromosomal anomalies associated with the diagnosis of schizophrenia were identified using cytogenetic techniques. Indeed, VCFS, XXX, XXY (Kleinfelter’s syndrome), and XO (Turner syndrome) have been found with similarly increased frequency in cases with this diagnosis in a number of studies. Now that we have greater resolution to identify smaller structural anomalies, the list of congenital syndromes that increase the possibility that people will manifest symptoms that earn them this diagnosis appears to be growing rapidly. Are we finding causes for the form of schizophrenia that most psychiatrists see in their offices, or are we instead carving out a new set of rare congenital syndromes that share some clinical characteristics, as syphilis was carved out from the diagnosis of schizophrenia at the turn of the twentieth century? Is schizophrenia a primary expression of these anomalies or a secondary manifestation? VCFS is associated with schizophrenia-like phenomena but even more often with mild mental retardation, autism spectrum, and other psychiatric manifestations. The same is true of the aneuploidies that increase the probability of manifesting schizophrenia symptoms. The two new papers in Nature allude to the possibility that epilepsy and intellectual limitations may also be associated with these CNVs. The diagnostic potential of any of these new findings cannot be determined until the full spectrum of their clinical manifestations is clarified.
One of the important insights that might emerge from identification of these new CNV syndromes is the identification of candidate genes that may show association with schizophrenia based on SNPs in these regions. VCFS has been an important source of promising candidate genes with broader clinical relevance (e.g., PRODH, COMT). Stefansson et al. report, however, that none of the 319 SNPs in the CNV regions showed significant association with schizophrenia in quite a large sample of individuals not having deletions in these regions. The Consortium report also presumably has the results of SNP association testing in these regions in their large sample but did not report them. It is very important to explore in greater genetic detail these regions of the genome showing association with the diagnosis of schizophrenia in samples lacking these lesions and to fully characterize the clinical picture of individuals who have them. It is hoped that insights into the pathogenesis of symptoms related to this diagnosis will emerge from these additional studies.
Anyone who has worked in a public state hospital or chronic schizophrenia care facility (where I spent over 20 years) is not surprised to find an occasional patient with a rare congenital or acquired syndrome who expresses symptoms similar to those individuals also diagnosed with schizophrenia who do not have such rare syndromes. Our diagnostic procedures are not precise, and the symptoms that earn someone this diagnosis are not specific. Schizophrenia is not something someone has; it is a diagnosis someone is given. In an earlier comment for SRF on structural variations in the genome related to autism, I suggested that, “From a genetic point of view, autism is a syndrome that can be reached from many directions, along many paths. It is not likely that autism is any more of a discrete disease entity than say, blindness or mental retardation.” These new CNV syndromes manifesting schizophrenia phenomena are probably a reminder that the same is true of what we call schizophrenia.
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Related News: Schizophrenia-associated Variant in ZNF804A Gene Affects Brain Connectivity
Comment by: James Walters, Michael Owen (SRF Advisor)
Submitted 3 June 2009
Posted 3 June 2009
Andreas Meyer-Lindenberg’s group examine the association between a single nucleotide polymorphism (SNP), rs1344706 in gene ZNF804A, recently identified as a risk factor for schizophrenia in a genome-wide association study (GWAS) (O'Donovan et al., 2008) and functional connectivity as measured by fMRI. The attraction of this polymorphism for a study of this kind is twofold. First, statistically speaking it is the most robust SNP association with schizophrenia reported to date. Second, because a single variant shows strong evidence for association, which is not the case for other reported associations, it is possible to specify a priori for the gene in question directional hypotheses in relation to potential neurocognitive correlates. This militates against the generation of false positives through the testing of multiple SNPs and haplotypes which has rendered problematic the interpretation of at least some previous genetic imaging studies (Walters and Owen, 2007). The function of ZNF804A is unknown but the fact that it contains a zinc finger domain suggests that it may be a transcription factor. It is hoped that the characterization of the actions of SNPs identified by GWAS will identify new pathogenic mechanisms of psychosis. One way in which this can be achieved is via approaches such as that taken in this article.
Esslinger et al. report variations in functional connectivity in 115 healthy individuals according to rs1344706 risk variant status. Given the association of ZNF804A with both schizophrenia and bipolar disorder they employed two fMRI tasks thought to be sensitive to altered function in these disorders: the N Back (2back) task is sensitive to deficits of dorsolateral prefrontal cortex (DLPFC) function in schizophrenia and an emotional face-matching task is linked with amygdala function and thought to be relevant to mood disorder. They compared the activity in these regions and functional connectivity (using time-series correlation) between the three rs1344706 genotype groups.
No differences between genotype groups were found for activation, but the authors did identify altered connectivity with the most activated DLPFC locale. Risk-allele carriers were shown to exhibit a lack of uncoupling of activity (increased functional connectivity) between the right DLPFC and left hippocampus during the 2-back task as well as decreased connectivity within right DLPFC and between right and left DLPFC. Risk variant carriers also showed wide ranging increased connectivity between right amygdala and other anatomical regions. The majority of these findings showed a risk allele dose effect.
The increased DLPFC/hippocampus functional connectivity in carriers of the risk allele is potentially the most interesting finding given that Meyer-Lindenberg’s group has previously shown that those with schizophrenia show increased functional connectivity between DLPFC and hippocampus during working memory (Meyer-Lindenberg et al., 2005). Notes of caution in this regard are that 1) the biological, anatomical or functional significance of fMRI determined functional connectivity is yet to be established and 2) other functional connectivity studies in schizophrenia have produced conflicting results Lawrie et al., 2002. Nonetheless, it is interesting that rs1344706 may affect co-ordination of activity between these two brain regions given their seeming importance in psychotic conditions. The significance of these findings to cognitive deficits and other symptom domains needs further investigation particularly as others have postulated dysconnectivity has more relevance to first rank psychotic symptoms (Stephan et al., 2009).
It is likely that genome-wide association approaches will continue to identify genes with unknown neural function and so approaches such as this are likely to be a valuable way of identifying the biological/neural pathways that involve these genes. It is also imperative that as in this study methodology is employed to allow for multiple testing and also that negative findings are reported. We would also suggest caution until these findings are replicated. As well as such approaches in humans, it is also important to investigate the effects of identified variants at other levels of analysis from gene expression to behavioural genetics work. Finally we find it reassuring that GWAS approaches seem to be successful in identifying risk variants whose functions can be investigated using methods such as that taken by Esslinger et al.
O'Donovan MC, Craddock N, Norton N, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics. 2008;40(9):1053-1055. Abstract
Walters JT, Owen MJ. Endophenotypes in psychiatric genetics. Mol Psychiatry. 2007;12(10):886-890. Abstract
Meyer-Lindenberg AS, Olsen RK, Kohn PD, et al. Regionally Specific Disturbance of Dorsolateral Prefrontal-Hippocampal Functional Connectivity in Schizophrenia. Archives of General Psychiatry. 2005;62(4):379-386. Abstract
Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry. 2002;51(12):1008-1011. Abstract
Stephan KE, Friston KJ, Frith CD. Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring. Schizophr Bull. 2009;35(3):509-527. Abstract
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Related News: Schizophrenia Genetics 2: The Rise of GWAS
Comment by: Chris Carter
Submitted 7 April 2010
Posted 8 April 2010
I wonder whether the relative lack of success in schizophrenia GWAS may be because the origin of schizophrenia may lie not so much in the genetic make-up of people with schizophrenia themselves, but in their prenatal experience, and possibly with the genes of the mother rather than with those of the offspring. Famine, rubella, influenza, herpes (HSV1 and HSV2), and poliovirus infection as well as high fever during pregnancy have all been listed as risk factors for the offspring developing schizophrenia in later life, as have maternal preeclampsia and obstetric complications. (See page at Polygenic Pathways for the many references.)
Maternal resistance to these effects is likely to be gene-dependent. Is it worth considering GWAS in the mothers rather than in the offspring?
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Related News: Bone Marrow and Aspirin: New Ingredients in Biological Psychiatry
Comment by: Christopher Pittenger
Submitted 18 June 2010
Posted 22 June 2010
I recommend the Primary Papers
The recent study from the Capecchi laboratory, in which the excessive grooming phenotype observed in HoxB8 knockout mice (Greer and Capecchi, 2002) was found to be mediated by the absence of HoxB8 in hematopoietically derived cells rather than in neurons, represents a startling and important advance. It comes as a surprise to many in the community—certainly to me—that a phenotype as specific and ethologically relevant as syntactic grooming would be modifiable by a specific alteration in microglia. And yet this is precisely what the new paper shows—and shows with very elegantly designed and performed experiments, which leave little doubt as to the striking conclusion. This study will increase interest in the interaction between immune or inflammatory processes and specific behaviors in a variety of basic and pathological contexts, and this is a salubrious advance in the field.
More vexing is the question of whether or not these mice in general, and the new finding in particular, advance our understanding of any specific neuropsychiatric condition. The mice have been described, in the title of the original paper and in numerous contexts since, as a potential mouse model of obsessive-compulsive disorder (OCD). This is a provocative assertion, and it requires careful consideration.
Certainly the idea of a deep connection between an aberrant immune response in the brain and the symptoms of OCD is not a new one. P.A.N.D.A.S. (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus) is a pediatric syndrome (still somewhat controversial) in which symptoms of OCD begin rather suddenly after a streptococcal infection in a susceptible child and then follow an episodic course, with exacerbations triggered by subsequent infections (Swedo et al., 1998). Localized brain inflammation triggered by autoantibodies, analogous to rheumatic fever and Sydenham’s chorea, represents the hypothesized causal link. Some authors have suggested that such an autoimmune pathogenesis may also be at play in adult OCD and not just in a small subset of pediatric-onset disease (e.g., Bhattacharyya et al., 2009). The new HoxB8 study, which produces a compulsive behavior through unclear actions (or lack of action) by HoxB8-deficient microglia, is quite different from such an autoantibody-mediated pathogenesis, but it resonates with the hypothesized connection between dysregulation of the immune system and OCD symptomatology.
However, the connection to OCD is based on an intuitive resemblance of the observed excessive grooming to repetitive and inflexible behaviors seen in OCD—that is, to the “face validity” of the model. Face validity can be a fickle guide in models of psychiatric disease. For example, excessive grooming has been described as OCD-like in other contexts (e.g., Welch et al., 2007), but it could as easily be interpreted as a model of trichotillomania, autistic stereotypy, Tourette syndrome, amphetamine-induced stereotypy, drug habit, or something ethologically unique to mice. Grooming is a particularly difficult phenotype to interpret in a cross-species comparison as it is quite variable among species—rodent grooming is quite different from primate grooming—and presumably subject to substantial selective pressure, due both to ecological and social factors (not to mention the presence or absence of fur). Therefore, the mere fact that the animals groom excessively is a slim basis for describing them as a model of OCD.
Recent studies have tried to extend the face validity of similar proposed models in other genetically modified mice by examining anxiety. For example, anxiety along with excessive grooming is seen in mice with a mutation in SAPAP3 (Welch et al., 2007) or with SliTrk5 (Shmelkov et al., 2010). Since OCD is categorized in DSM-IV as an anxiety disorder and often presents with significant anxiety (although not always, in my experience), this additional phenotype strengthens the face validity of the model. Even so, such face-validity comparisons are best considered as analogies to human conditions. It is far from clear that observable measures of anxiety in a mouse adequately parallel the psychic and cognitive type of anxiety experienced by patients with OCD. Furthermore, anxiety is an extraordinarily non-specific psychiatric symptom—I often ask residents, as an exercise, to name psychiatric disorders that are not frequently characterized by anxiety, and they are hard pressed to come up with more than a handful.
An additional evaluation uses predictive validity—that is, the ability of medications used to treat OCD to ameliorate the observed phenotypes. This was done in the studies of both the SAPAP3 and SliTrk5 mice, referenced above, in which SSRIs were found to ameliorate both excessive grooming and anxiety phenotypes. Such a predictive validity test also has significant weaknesses, however, because of the imprecise nature of both psychiatric diagnosis and psychiatric pharmacotherapy. SSRIs are of benefit in only 50-60 percent of cases of OCD, even with optimal dosing (see, e.g., Bloch et al., 2009). And SSRIs are also used to treat depression, generalized anxiety disorder, social anxiety disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, bulimia, anorexia, and a host of other conditions. Therefore, response to an SSRI does not validate a mouse model as recapitulating core aspects of the neurobiology of OCD, and lack of response should not be interpreted as particularly undermining of a model’s validity.
Ultimately, the most valid models of OCD, or of any other neuropsychiatric condition, will be those based on confirmed aspects of the neurobiology of the disorder, such as well-validated genes of large effect size, specific molecular or cellular changes strongly and specifically associated with the disorder, or environmental stressors or insults with a similarly specific association. Such toe-holds into the pathophysiology of the disorder can be leveraged by carrying them over to animal models in which their downstream consequences, and potential ameliorative therapies, can be examined. Obviously, such validated hints of the pathophysiology of disease are few and far between in neuropsychiatric conditions, and virtually absent in obsessive-compulsive disorder, a relatively under-studied condition. In my view, until we have such biological grounding on which to base the construct validity of our models, it is best not to describe these or any other mice as representing “an animal model of OCD.” It is better to speak of an animal that exhibits excessive grooming, plain and simple. The relationship to OCD, or any other human neuropsychiatric condition, remains an empiric question that will be challenging to answer in a satisfying way.
However, this comment does not detract in any scientifically important way from the importance of the recent paper from the Capecchi group. They have certainly provided a valuable examination of an animal that exhibits maladaptively excessive and inflexible grooming. In addition, their striking finding of the critical role of microglia in producing this phenotype is of profound importance and will push the field towards a deeper appreciation of the importance of immune-brain interactions, not only for general brain health, but for the development and modulation of specific phenotypes. This is an exciting finding indeed.
Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron . 2002 Jan 3 ; 33(1):23-34. Abstract
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