News Brief: More CNVs for Schizophrenia
20 December 2011. Looking in a new Bulgarian sample, researchers conducted a study, published online in Molecular Psychiatry on November 15, finding that de novo copy number variations (CNVs) occurred more frequently in schizophrenia patients than in controls. This news, presented earlier this year at the World Congress of Psychiatric Genetics (see SRF related news story), adds to the evidence that the loss or gain of a chromosome segment elevates risk for schizophrenia and other brain disorders (see SRF related news story), and makes a case for de novo CNVs—those spontaneously occurring in germ cells rather than being inherited from parents—as factors behind sporadic cases of schizophrenia.
Led by Michael Owen of Cardiff University in the U.K., the researchers screened 662 individuals with schizophrenia and both parents for CNVs, and turned up 34 de novo events; these were more frequent in cases (5.1 percent) compared to 2,623 controls (2.2 percent). Eight of the de novo CNVs occurred at locations already linked to schizophrenia (3q29, 15q11.2, 15q13.3, and 16p11.2), whereas others landed in new regions and genes, including members of the DLG family found in the post-synaptic density, where they are involved in getting receptors, ion channels, and signaling proteins to their proper locations. Two other CNVs implicated EHMT1, a gene encoding a histone methyltransferase reported to directly regulate DLG members (Kramer et al., 2011).
Undertaking gene-set analysis to get a picture of the kinds of genes affected by these CNVs, the researchers found that CNVs in schizophrenia cases tended to hit genes encoding post-synaptic density proteins more frequently than controls (P = 1.72 x 10-6), with genes for the activity-regulated cytoskeleton-associated protein complex (ARC) and the NMDA receptor complex contributing the bulk of this enrichment. An independent analysis of a large dataset comprising 17,907 cases and 10,585 controls revealed a similar picture, with de novo CNVs landing in NMDA receptor complex genes in schizophrenia more frequently than controls (P = 0.0015). This finding supports the idea that disruptions to NMDA receptor signaling may lay the groundwork for schizophrenia (see SRF Hypothesis).—Michele Solis.
Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, Moran J, Chambert K, Toncheva D, Georgieva L, Grozeva D, Fjodorova M, Wollerton R, Rees E, Nikolov I, van de Lagemaat LN, Bayés A, Fernandez E, Olason PI, Böttcher Y, Komiyama NH, Collins MO, Choudhary J, Stefansson K, Stefansson H, Grant SG, Purcell S, Sklar P, O'Donovan MC, Owen MJ. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2011 Nov 15. Abstract
Comments on Related News
Related News: WCPG 2011—A Capital Day for CNVs in SchizophreniaComment by: John McGrath, SRF Advisor
Submitted 17 September 2011
Posted 20 September 2011
De novo CNVs are associated with advanced paternal age in a mouse model
While the association between advanced paternal age and an increased risk of various neuropsychiatric disorders such as schizophrenia and autism is now well established, the mechanism underpinning this finding remains unclear. Putative mechanisms include de-novo mutations and/or epigenetic mechanisms. In light of the growing body of evidence linking copy number variants (CNVs) with these same disorders, we used a mouse model to explore the hypothesis that the offspring of older males have an increased risk of de-novo CNVs. C57BL/6J sires that were three- and 12-16 months old were mated with three-month-old dams to create control offspring and offspring of old sires, respectively. Applying genomewide microarray screening technology, seven distinct CNVs were identified in a set of 12 offspring and their parents.
Competitive quantitative PCR confirmed these CNVs in the original set and also established their frequency in an independent set of 77 offspring and their parents. On the basis of the combined samples, six de-novo CNVs were detected in the offspring of older sires, whereas none were detected in the control group. Two of the CNVs were associated with behavioral and/or neuroanatomical phenotypic features. One of the de-novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism, and brain development.
Our results support the hypothesis that the offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism by generation of de-novo CNVs in the male germline.
T Flatscher-Bader, CJ Foldi, S Chong, E Whitelaw, RJ Moser, THJ Burne, DW Eyles, JJ McGrath. (2011) Increased de novo copy number variants in the offspring of older males. Translational Psychiatry. View the free full-text article.
View all comments by John McGrath
Related News: Altered Gene Expression Prioritizes CNVs in Autism
Comment by: Karoly Mirnics, SRF Advisor
Submitted 16 July 2012
Posted 16 July 2012
This is another excellent genomics study from the Geschwind laboratory, challenging us to think in the context of gene networks (rather than single genes). We always knew that genome deletion, duplications, and mutations will have an effect on development and cellular function only if they ultimately affect gene expression, but rarely has this been proven so eloquently as in this study. Knowing a genetic alteration is not sufficient—the consequences are what matter—and establishing the relevance/causality of mutations and CNVs vis-à-vis a disease process is quite challenging. Combining genetics and genomics can help to achieve this, especially if the expression studies can be performed on peripheral tissues from living patients. Still, even this approach has limitations: the brain has a very different expression profile from peripheral tissues—and the real effect of altered genetic sequence cannot be evaluated if a gene is uniquely expressed in the brain. Furthermore, we know that in schizophrenia, expression events in the periphery and the CNS are only marginally overlapping, and a number of neurotransmitters and phenotype-specific functional proteins are not expressed outside of the brain. In these cases, inhibitory postsynaptic currents (IPSCs) might be very beneficial to study the cause-effect relationship and in evaluating the significance of the genetic alterations. However, the approach of the Geschwind lab is perfectly suited for evaluation of multifunctional, generic developmental gene networks, where the genes are expressed and play a similar role across various tissues. It is also important to expand these studies to many patients across a variety of human brain disorders; otherwise, due to the staggering number of genetic variations, we might not be able to recognize the common patterns that are essential for understanding mental disorders.
View all comments by Karoly Mirnics
Related News: Dissecting Cognition at the Synapse
Comment by: Jennifer Barnett (Disclosure)
Submitted 13 December 2012
Posted 13 December 2012
Cognitive function is highly heritable (Devlin et al., 1997), yet we have relatively little understanding of which genes regulate either general intelligence or specific cognitive functions. A long list of mutations can cause the large cognitive impairments that we class as learning disability—including many of the same CNVs associated with cognitive disorders such as autism and schizophrenia (Guilmatre et al., 2009). Prior to the GWAS era, it was generally assumed that normal variation—outside of the range of learning disability—would be regulated by common variants of small effect. Yet GWAS, a technology well suited to detecting common variants of small effect, has not massively increased our understanding of the genetic basis of cognition.
One explanation for this relative lack of success is that, compared with quantitative phenotypes such as height or BMI, the measurement of cognition can be time consuming and therefore costly, so really large-scale studies are rare. Moreover, any two studies are very unlikely to use identical cognitive tests, introducing error to the phenotypic measurement and making it difficult to combine datasets. In this context, the Nithianantharajah paper is a beautiful example of how translational research using relatively simple but neuroscience-led assays can increase our understanding of the genetics of cognition, while avoiding the need for the ever-increasing sample sizes.
In particular, I was impressed by the building up of related but increasingly complex forms of cognition across the rodent tasks, and the use of the closest possible analogues between mouse and human assays. (Disclosure: I am employed by Cambridge Cognition, the suppliers of the CANTAB tests used in the human phenotyping.) Adding to these very careful phenotyping methodologies, the parallel experiment across both mouse and human "knockouts" is a really elegant piece of translational neuroscience.
Like many traits underlying brain function, it is inherently easy to believe that variants that have large effects on cognition would create strong evolutionary advantages or disadvantages. The authors here demonstrate not only that a related family of genes affects multiple aspects of cognitive function, but also that variation in these genes produces different cognitive tendencies in the mouse, including reciprocal effects of variants of Dlg2 and Dlg3, which seem, at least at first pass, to be conserved in human behavior.
There is a lot to digest in this and the companion paper by Ryan et al., but the methodology appears to have been very useful here in understanding cognition, and may provide useful insights for researchers trying to decipher other aspects of the schizophrenia phenotype.
Devlin B, Daniels M, Roeder K (1997). The heritability of IQ. Nature.388(6641):468-71. Abstract
Guilmatre A, Dubourg C, Mosca AL, Legallic S, Goldenberg A, Drouin-Garraud V, Layet V, Rosier A, Briault S, Bonnet-Brilhault F, Laumonnier F, Odent S, Le Vacon G, Joly-Helas G, David V, Bendavid C, Pinoit JM, Henry C, Impallomeni C, Germano E, Tortorella G, Di Rosa G, Barthelemy C, Andres C, Faivre L, Frébourg T, Saugier Veber P, Campion D. (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry;66(9):947-56. Abstract
View all comments by Jennifer Barnett
Related News: New Exome Evidence Points to Old Suspect in Schizophrenia
Comment by: Francis McMahon, SRF Advisor
Submitted 23 January 2014
Posted 28 January 2014
I think these studies do represent real progress. Finding genetic support for particular pathways provides unique evidence for a causative role of these pathways in disease. Why didn't the case-control study point to individual genes? Disorders such as schizophrenia may be more like a plane crash than a typical inherited disease: Since many things can go wrong, each crash is different, but damage to key systems is very likely to lead to a bad outcome. The finding in Fromer et al. that there are 18 genes with recurrent deleterious de novo events should allow scientists to focus on these genes as especially important. The overlaps with autism and intellectual disability are interesting, though not entirely unexpected. Will we also see gene overlaps with illnesses such as bipolar disorder? It wouldn't surprise me if some of the same genes are involved, but with fewer, less deleterious hits.
View all comments by Francis McMahon