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