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The Mixed Economy of Schizophrenia Genetics Grows in Different Sectors

4 May 2010. Rare mutations in the SHANK3 gene crop up in schizophrenia, according to a report published April 27 in PNAS. Researchers found de novo point mutations in the gene in two families, a finding that adds to the burgeoning catalog of genetic variants—both rare and common—found in schizophrenia. Here we give a brief rundown of the SHANK3 study along with other recent findings that involve common variants in ZNF804A and AHI1, and rare variants in ABCA13. This spate of studies supports the notion of a mixed economy of genetic variation in schizophrenia (see SRF related news story), and in some cases, identifies the same variant in more than one disorder.

Led by Guy Rouleau at the University of Montreal in Canada, the researchers sequenced the protein-coding portions of the SHANK3 gene in 285 controls and 185 cases of sporadic schizophrenia, meaning that the subjects’ parents did not have the disorder. The investigators focused on SHANK3 because of its role in forming dendritic spines—the small protrusions that receive signals from other neurons across a glutamatergic (excitatory) synapse—and also because the gene has already been implicated in autism (Durand et al., 2007). The study is part of the team's ambitious plan to screen 1,000 genes encoding synaptic proteins for mutations in people with brain disorders such as schizophrenia, autism, and mental retardation.

First author Julie Gauthier and colleagues found two point mutations in two unrelated families with schizophrenia. In one family, the point mutation occurred in three affected brothers, making it likely that the mutation originated from one parent's germ cells. This mutation resulted in a prematurely truncated protein, and functional assays of the protein in zebrafish and rat hippocampal neurons suggested that the mutation disrupts synaptic function and inhibits the formation of neuronal processes. Though the other point mutation in the second family seemed less disruptive in these assays, it did result in an amino acid substitution that deserves closer examination.

The authors point out that the four people carrying these mutations were at the severe end of the schizophrenia spectrum: some had an early age of onset, and all had varying degrees of mental retardation beforehand. Whether SHANK3 mutations like these also occur in more typical cases remains to be seen. If not, then SHANK3 mutations may be restricted to severe cases that often come with other neurodevelopmental diagnoses, and this could explain the overlap of SHANK3 mutations found in both schizophrenia and autism.

But common variation hangs in there
Despite this new evidence for rare but nasty genetic changes in schizophrenia (see SRF related news story), the case for common variants with modest risk stays in the running (see SRF related news story). A recent genomewide association study (GWAS) and two other reports published in Molecular Psychiatry find a compelling association between a particular single nucleotide polymorphism (SNP) in the ZNF804A gene and schizophrenia (see ZNF804A)—confirmation of the original finding (O'Donovan et al., 2008). The earlier study, from Michael O'Donovan and Michael Owen and colleagues at Cardiff University, United Kingdom, turned up an association between SNP rs1344706 and schizophrenia, which strengthened when cases of bipolar disorder were also included (see SRF related news story).

The new studies echo these findings about ZNF804A, a putative transcription factor, by converging on the same SNP, finding similar effect sizes, and documenting an overlap with bipolar disorder. In a study published on April 6, first author Hywel Williams and the team at Cardiff University carefully looked for other SNPs in the ZNF804A gene associated with schizophrenia, but their original rs1344706 still rose to the top. They then pooled several datasets to compare rs1344706 genotypes in notably large samples: 18,945 cases of schizophrenia, 21,274 cases of schizophrenia or bipolar disorder, and a whopping 38,675 controls. This resulted in highly significant associations, and odds ratios of 1.10 for schizophrenia and 1.11 for schizophrenia combined with bipolar disorder.

A report in January from Brien Riley at Virginia Commonwealth University and colleagues also trolled for associations among 12 SNPs along ZNF804A and schizophrenia in the Irish Case-Control sample, consisting of 1,021 cases of schizophrenia and 626 controls. Again, rs1344706 turned up with an odds ratio of 1.20. Another January study, from first author Stacy Steinberg of deCODE Genetics in Iceland and colleagues around the world, reported a replication of this same association, getting an odds ratio of 1.08 with 5,164 schizophrenia cases and an odds ratio of 1.09 when 609 bipolar cases were included with the schizophrenia group. The team also found copy number variations (CNVs)—deletions or duplications of DNA—involving the ZNF804A gene in three cases of psychiatric disorders, a reminder that SNPs themselves can be used to identify regions harboring rarer variants.

Something old, something new
This uplifting series of replications—GWAS hits frequently fail to hold up to further scrutiny—extends to another gene, AHI1, in a study published April 1 in Human Molecular Genetics. Encoding a protein somehow important for brain development, AHI1 first came to light in a family study of schizophrenia (Amann-Zalcenstein et al., 2006); soon after, SNPs along the gene were associated with schizophrenia in a case control study (Ingason et al., 2007). In the new report, first author Andrés Ingason of Copenhagen University Hospital, Denmark, and colleagues found that seven SNPs along the AHI1 locus in a new European sample were overrepresented in a group of 3,907 schizophrenia cases compared to 7,429 controls. When the team organized a meta-analysis, combining data from multiple European samples to give 4,496 affected and 18,920 controls, the associations remained.

Amid these replications of earlier findings, new candidate genes continue to turn up, like SHANK3 or ABCA13—a gene fingered in a study late last year in American Journal of Human Genetics (Knight et al., 2009; see SRF related news story). ABCA13 initially drew the attention of first author Helen Knight and colleagues at University of Edinburgh, United Kingdom, when they found chromosomal abnormalities involving the gene in a person with schizophrenia. Sequencing the exons of the gene in 100 controls and 100 schizophrenia patients brought them 10 rare variants, which proved to be overrepresented in another sample of schizophrenia and bipolar patients. This suggests that single genes might have multiple variants that may each carry a different type of risk.

Whether identifying new candidate genes, describing the relevant alleles, or replicating the previously fingered ones in new or larger samples, together these studies argue that there is a place for both common, modest-risk variants and the rare, deleterious ones in the complicated landscape of schizophrenia genetics.—Michele Solis.

Gauthier J, Champagne N, Lafrenière RG, Xiong L, Spiegelman D, Brustein E, Lapointe M, Peng H, Côté M, Noreau A, Hamdan FF, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Joober R, Fathalli F, Mouaffak F, Haghighi AP, Néri C, Dubé MP, Samuels ME, Marineau C, Stone EA, Awadalla P, Barker PA, Carbonetto S, Drapeau P, Rouleau GA; S2D Team. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A. 2010 Apr 27;107: 7863-7868. Abstract

Williams HJ, Norton N, Dwyer S, Moskvina V, Nikolov I, Carroll L, Georgieva L, Williams NM, Morris DW, Quinn EM, Giegling I, Ikeda M, Wood J, Lencz T, Hultman C, Lichtenstein P, Thiselton D, Maher BS; Molecular Genetics of Schizophrenia Collaboration (MGS) International Schizophrenia Consortium (ISC), SGENE-plus, GROUP, Malhotra AK, Riley B, Kendler KS, Gill M, Sullivan P, Sklar P, Purcell S, Nimgaonkar VL, Kirov G, Holmans P, Corvin A, Rujescu D, Craddock N, Owen MJ, O'Donovan MC. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry. 2010 Apr 6. Abstract

Riley B, Thiselton D, Maher BS, Bigdeli T, Wormley B, McMichael GO, Fanous AH, Vladimirov V, O'Neill FA, Walsh D, Kendler KS. Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample. Mol Psychiatry. 2010 Jan; 15: 29-37. Abstract

Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, Andreassen OA, Sigurdsson E, Thorgeirsson TE, Böttcher Y, Olason P, Ophoff RA, Cichon S, Gudjonsdottir IH, Pietiläinen OP, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Athanasiu L, Suvisaari J, Lonnqvist J, Paunio T, Hartmann A, Jürgens G, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Breuer R, Möller HJ, Giegling I, Glenthøj B, Rasmussen HB, Mattheisen M, Bitter I, Réthelyi JM, Sigmundsson T, Fossdal R, Thorsteinsdottir U, Ruggeri M, Tosato S, Strengman E; GROUP, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Walshe M, Bramon E, Vassos E, Li T, Fraser G, Walker N, Toulopoulou T, Yoon J, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MM, Rietschel M, Peltonen L, Rujescu D, Collier DA, Stefansson H, St Clair D, Stefansson K. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2010 Jan 5. Abstract

Ingason A, Giegling I, Cichon S, Hansen T, Rasmussen HB, Nielsen J, Jürgens G, Muglia P, Hartmann AM, Strengman E, Vasilescu C, Mühleisen TW, Djurovic S, Melle I, Lerer B, Möller HJ, Francks C, Pietiläinen OP, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Walshe M, Vassos E, Di Forti M, Murray R, Bonetto C, Tosato S; GROUP Investigators, Cantor RM, Rietschel M, Craddock N, Owen MJ, Peltonen L, Andreassen OA, Nöthen MM, St Clair D, Ophoff RA, O'Donovan MC, Collier DA, Werge T, Rujescu D. A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia. Hum Mol Genet. 2010 April; 19:1379-1386. Abstract

Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K, van Beck M, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St Clair D, Muir WJ, Blackwood DH. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet. 2009 Dec; 85: 833-846. Abstract

Comments on News and Primary Papers

Primary Papers: Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample.

Comment by:  David J. Porteous, SRF Advisor
Submitted 28 October 2009
Posted 29 October 2009
  I recommend this paper

Sorting wheat from chaff in genomewide association studies may well entail more time and effort than the original study. It is therefore important to critically evaluate results from truly independent data sets and, as this study attempts, to take the analysis beyond just statistical association toward some sort of functional analysis. That said, this would appear to be a fairly dramatic example of winner's curse, for the strength of association reported in the Irish sample would not have warranted even the briefest mention in the original Cardiff study (O'Donovan et al., 2008).


O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V, Nikolov I, Hamshere M, Carroll L, Georgieva L, Dwyer S, Holmans P, Marchini JL, Spencer CC, Howie B, Leung HT, Hartmann AM, Möller HJ, Morris DW, Shi Y, Feng G, Hoffmann P, Propping P, Vasilescu C, Maier W, Rietschel M, Zammit S, Schumacher J, Quinn EM, Schulze TG, Williams NM, Giegling I, Iwata N, Ikeda M, Darvasi A, Shifman S, He L, Duan J, Sanders AR, Levinson DF, Gejman PV, Cichon S, Nöthen MM, Gill M, Corvin A, Rujescu D, Kirov G, Owen MJ, Buccola NG, Mowry BJ, Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Cloninger CR; Molecular Genetics of Schizophrenia Collaboration. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet. 2008 Sep;40(9):1053-5. Abstract

View all comments by David J. Porteous

Primary Papers: De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.

Comment by:  Atsushi Kamiya
Submitted 4 May 2010
Posted 4 May 2010

Gauthier and colleagues report additional genetic evidence supporting “synapse” pathology for schizophrenia. They discovered two de novo mutations in SHANK3, which encodes a scaffold protein in the post-synaptic density of excitatory synapses. The first mutation is a nonsense mutation (R1117X) in a patient with schizophrenia and his two brothers with schizophrenia and schizoaffective disorder. The second mutation is a missense mutation (R536W) in a patient with schizoaffective disorder. Furthermore, the effect of both mutations in SHANK3 was functionally tested in vivo and in vitro with zebrafish behavior and rat hippocampal neuronal culture. The impairment of swimming activity by the morpholino-mediated knockdown of the ortholog of SHANK3 was partially rescued by the R536W mutant, and was not rescued by the R1117X mutant. Overexpression of wild-type SHANK3 and the R536W mutant stimulate neurite outgrowth in rat hippocampal neurons, but the R1117X mutant does not. These findings, taken together, lead the authors to conclude that the R1117X mutation has a loss-of-function effect.

Although their findings may only account for rare cases of the disease condition, it is expected that their findings will be replicated in different populations. Such rare de novo or inheritance mutations, however, may have a strong biological impact, and they are useful to address potential molecular disease pathways. Given that SHANK3, at the synaptic region, is known to interact, or potentially interacts, with other genetic risk factors for schizophrenia and autism, such as neurexin-1, neuroligin-3, and -4, neuregulin-1, ErbB4, and DISC1, the convergence of synaptic signaling disturbances may account for the pathophysiologies of these devastating conditions. The question that arises is how such genetic disturbances lead to a wide range of mental disorders, such as schizophrenia and autism, which are sometimes complicated by mental retardation. Could other genetic risks and/or environmental factors define the final disease phenotypes? How can we address this question by utilizing animal models? The typical onset of schizophrenia is in late adolescence or early adulthood, whereas patients with autism are usually first diagnosed in early childhood. The different time courses of schizophrenia and autism should be considered in animal studies at the molecular, neuronal circuit, and behavioral levels.

View all comments by Atsushi Kamiya

Comments on Related News

Related News: More Evidence for CNVs in Schizophrenia Etiology—Jury Still Out on Practical Implications

Comment by:  Christopher RossRussell 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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View all comments by Russell L. Margolis

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.

View all comments by Daniel Weinberger

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?

View all comments by Chris Carter

Related News: News Brief: Schizophrenia Gene Suspect Affects Fetal Brain

Comment by:  Michael O'Donovan, SRF Advisor
Submitted 11 January 2013
Posted 11 January 2013

Hill and Bray report mRNA expression analysis of the schizophrenia risk gene ZNF804A in adult and fetal brain. Importantly, they used an allele-specific expression assay that allows them to isolate cis-acting effects influencing ZNF804A expression (cis effects on expression are those which are restricted to the particular copy of a gene carrying the feature that influences expression, for example, a regulatory polymorphism at the gene locus) from artifacts related to RNA quality and more general trans-effects on gene expression (trans-effects influence expression of both copies and may arise as a result of environmental exposures such as drugs, or variable levels of a transcription factor). As a result, they were able to sensitively search for possible relationships between gene expression and genotype at rs1344706, the ZNF804A single-nucleotide polymorphism (SNP) that is currently the most strongly schizophrenia-associated variant (see Williams et al., 2011). Previous work by Williams and colleagues using similar methodology to that of Hill and Bray had shown that in adult brain, chromosomes carrying the schizophrenia risk allele at rs1344706 express ZNF804A at a higher level than those which do not carry the risk allele. However, the relationship between higher expression and genotype at rs1344706 was not perfect. Moreover, since another polymorphism at the ZNF804A locus was much better correlated with gene expression than rs1344706, but was only weakly associated with schizophrenia risk, Williams and colleagues concluded that the observed overexpression was not likely to be the mechanism underpinning the association between ZNF804A and schizophrenia.

In the present study, Bray and Hill reach the same conclusion with respect to adult brain. However, when they extended their work into fetal brain, a very different picture emerged. Specifically, in second-trimester fetal brain, chromosomes carrying rs1344706 were underexpressed. This is in stark contrast to the findings of higher expression in adult brain. Moreover, they also found that genotype at rs1344706 was strongly correlated with cis-measures of ZNF804A expression to an extent that is consistent with, although does not prove, the hypothesis that rs1344706 is, per se, the functional variant. The finding of a strong correlation between a schizophrenia risk allele and a gene function that is observed only in the second trimester of fetal development but not in adult brain supports the widely held hypothesis that the origins of schizophrenia, at least in part, begin during brain development. That conclusion is necessarily somewhat tentative since it is not established that the observed changes in expression are relevant to disease. However, the absence of protein-coding variants to explain the ZNF804A association, and the evidence from earlier work by the same authors (Hill and Bray, 2011) showing that binding of as yet unknown nuclear proteins to ZNF804A DNA is sensitive to genotype at rs1344706, make a good circumstantial case that it may be. Regardless, the demonstration of developmental specificity in the functional associations of a strongly implicated schizophrenia risk variant emphasizes the importance of studying regulatory effects of risk alleles at a range of developmental time points, and point to the need to augment genetic studies of gene expression with larger-scale studies using tissues from a range of developmental time points.


Hill MJ, Bray NJ. Allelic differences in nuclear protein binding at a genome-wide significant risk variant for schizophrenia in ZNF804A. Mol Psychiatry . 2011 Aug 1 ; 16(8):787-9. Abstract

Williams HJ, Norton N, Dwyer S, Moskvina V, Nikolov I, Carroll L, Georgieva L, Williams NM, Morris DW, Quinn EM, Giegling I, Ikeda M, Wood J, Lencz T, Hultman C, Lichtenstein P, Thiselton D, Maher BS, , Malhotra AK, Riley B, Kendler KS, Gill M, Sullivan P, Sklar P, Purcell S, Nimgaonkar VL, Kirov G, Holmans P, Corvin A, Rujescu D, Craddock N, Owen MJ, O'Donovan MC. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry . 2011 Apr ; 16(4):429-41. Abstract

View all comments by Michael O'Donovan

Related News: A Model Is a Model Is a Model of Mental Illness?

Comment by:  Kevin J. Mitchell
Submitted 7 November 2013
Posted 11 November 2013

Instead of asking whether a particular animal model is "valid" as a proxy for a particular psychiatric disorder, we should be asking, Is it useful? Can it tell us something we can't learn in humans? If we base that solely on supposed behavioral similarities, we haven't gotten very far—we might as well just be doing rodent psychoanalysis. What we are interested in is elucidating the underlying neurobiological abnormalities and the pathways from etiological factors to resultant pathophysiological states. Such states should be expected to affect behaviors in a species-specific manner—maybe there will be some surface similarity in the results between rodents and humans, but maybe not. Certainly, expecting any animal model to recapitulate the full profile of human symptoms associated with a particular psychiatric diagnostic category is asking too much—does any human patient model the entire spectrum of disease? If these diagnostic categories are really umbrella terms for hundreds of distinct genetic conditions, each with variable outcomes, then the focus in models should be more on the expression of particular symptom domains than on entire disease profiles.

Starting with strong etiological factors is a proven route to discovery of pathogenic mechanisms. As such, the SHANK3 duplication mice are more inherently relevant to disease than the calcineurin mice, which are an artificial transgenic line not directly representative of any human patient. Indeed, the genetic evidence implicating calcineurin in schizophrenia risk has effectively been superseded by negative results from very large GWASs (unless it has popped up again in the unpublished results of the PGC). It is, nevertheless, a very interesting genetic preparation that can be used to dissect circuit mechanisms of memory, which clearly are of relevance to several disease states. That really ought to be enough to garner a wide readership without resorting to claims of direct disease model validity.

View all comments by Kevin J. Mitchell

Related News: A Model Is a Model Is a Model of Mental Illness?

Comment by:  Barbara K. Lipska
Submitted 13 November 2013
Posted 15 November 2013

There is a classic catch-22 in an attempt to model schizophrenia (and other major mental disorders) as, on the one hand, the main purpose of creating a model is to discover the cause of illness (e.g., a genetic defect and the subsequent pathological processes underlying the disease), and on the other hand, it is unclear what to model because the etiology of schizophrenia is still not well understood. Many new models focus on genetic causes because of the strong evidence for heritability of mental illness and the recent discoveries of particular predisposing genes. It is also becoming clear that in most cases, no single gene is necessary or sufficient to cause the disease, but instead, common, low-penetrance genetic variants in more than one susceptibility gene, each contributing a small effect, act in combinations to increase the risk of illness. In some other cases it is possible that rare, but highly penetrant, mutations (i.e., point mutations, translocations, deletions) in single genes are responsible. It is also increasingly clear that there are interactions among susceptibility genes, and between genes and environmental factors that contribute to the risk for mental illness. Given all this, there is no doubt that the task of modeling schizophrenia in animals is formidably difficult.

It is further complicated by the fact that a gene-based animal model 1) may have to be related to a specifically human transcript and/or protein variant or variants artificially introduced into the animal; 2) will not exhibit abnormalities in all schizophrenia-related phenotypes (as animals will not have hallucinations or delusions); and 3) may require additional environmental manipulations to become fully penetrant at the behavioral level. We should thus perhaps accept the fact that a mouse model for an individual candidate gene will never be representative of the entire disorder, and at best it will reproduce either a subtype of the disorder or a particular aspect of a given phenotype. In that context, human cell-based models and studies of human brain tissues obtained postmortem from patients with mental illness (severely underutilized resources!) are perhaps better alternatives to gain insight into the origins and pathophysiology of these specifically human, challenging disorders.

View all comments by Barbara K. Lipska

Related News: A Model Is a Model Is a Model of Mental Illness?

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 12 November 2013
Posted 15 November 2013
  I recommend the Primary Papers

I think that we are often making a mistake if we directly declare what disease are we modeling. There are no "valid" animal models of human schizophrenia or other major psychiatric disorders, and most likely, there will never be—the mouse is not a human, and has a quite different lifestyle! Furthermore, the mouse and the human genetic diversity are quite distinct. Thus, talking about modeling physiological and pathophysiological processes is much more correct. Understanding behavioral modulation by the various interneuronal subtypes, evaluating the role of gene X on cortical lamination, or assessing the effects of factor Y on neuronal outgrowth are all disease-relevant, essential studies.

View all comments by Karoly Mirnics