Human Molecular Genetics Advance Access originally published online on September 2, 2003
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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R125-R133
DOI: 10.1093/hmg/ddg302
© 2003 Oxford University Press
Recent advances in the genetics of schizophrenia
Department of Psychological Medicine, Neuropsychiatric Genetics Unit, University of Wales College of Medicine, Health Park, Cardiff, CF14 4XN, UK
Received July 2, 2003; Accepted August 28, 2003
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTIONThe high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24–22, 1q21–22 and 13q32–34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21–22, 6q21–25, 22q11–12, 5q21–q33, 10p15–p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia.
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INTRODUCTION |
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Understanding the aetiology and pathogenesis of schizophrenia is one of the most important challenges facing medicine given the huge burden of disability this common, severe and usually lifelong disorder imposes. Some progress has been made and the currently prevailing view is that schizophrenia is a neurodevelopmental disorder resulting in abnormalities of synaptic connectivity (1). However, one of the few things we know for certain is that individual differences in susceptibility are largely genetic, with heritability estimates of
80% (2). Like other common disorders, the genetics are complex (3). However, schizophrenia researchers are faced with the additional obstacle of a disorder entirely defined by history and clinical examination, there being no investigations to confirm diagnosis, to separate the syndrome from unrelated disorders or to aid in sub-classification (4). These difficulties together with early failures to obtain clear replication of linkages led to increasing scepticism that genetic approaches would ever be successful. However, for the first time in 15 years of intensive international effort, there are signs of real progress. Several strong and well-established linkages have emerged and evidence implicating individual genes within some of the linked regions has been reported, and more importantly, replicated. These successes reflect not only advances in genomics and the availability of the draft human genome sequence but also a greater realisation of the likely complexity of the underlying genetic architecture of schizophrenia and its implications for study design and the interpretation of data. |
LINKAGE AND POSITIONAL CLONING |
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As the data from a large number of whole genome linkage studies has accumulated, so has the evidence implicating particular loci (Table 1). Three [6p24–22 (5),1q21–22 (6) and 13q32–34 (7)] have received both genome-wide evidence for linkage as well as supportive evidence from other studies (Table 1). Additionally, two studies (8,9) have reported genome wide evidence for linkage to 6q, but although there are other supportive data (Table 1), the evidence is distributed across at least 80 cM. While this may reflect imprecision in a single linkage signal, it is also possible that multiple loci are involved.
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As for other complex diseases, the linkage findings usually fall short of genome-wide significance and failures to replicate are common. Failure to replicate true linkages to loci of moderate effect are to be expected, given that the typical samples of between 20 and 100 families are well short of what is required for adequate power (10,11). It is therefore difficult to separate the true positive findings from the (presumed) false positives represented in Table 1. One solution, albeit imperfect (12) is meta-analysis. In a recent meta-analysis of 20 schizophrenia genome scans (13), the number of loci meeting aggregate criteria for significance was much greater than the number of loci expected by chance (P<0.001), revealing greater consistency than has been previously recognised. The authors concluded that schizophrenia loci are highly likely to be present in some, perhaps even all, of 2p–q, 5q, 3p, 11q, 6p, 1p–q, 22q11–12, 8p 20p, and 14pter–q13. Other regions were also implicated where the evidence was somewhat weaker. These were 16p–q, 18q, 10p, 15q, 6q and 17q. Another meta-analysis (14) found significant results only on chromosomes 8p, 13q and 22q. The two studies differed in many important respects, including the basic approach, but it seems reasonable that because it was based upon a larger and more complete dataset, the study by Lewis et al. (13) identified additional significant regions.
The evidence for multiple linkage regions in schizophrenia begs the question of which warrant extensive efforts aimed at identifying the susceptibility loci. This is a matter of weighing for each region the strength of the evidence, against cost and feasibility. In our view, linkages that meet genome-wide criteria for significance or in which several suggestively positive studies have been reported now merit follow up (Fig. 1). Unsurprisingly, this work has being going on in several laboratories for the last few years. More surprisingly to some, it is now beginning to yield findings of considerable interest.
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DYSTROBREVIN BINDING PROTEINDYSBINDIN (DTNBP1) |
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Straub et al. (15) undertook systematic LD mapping across linked regions on 6p, using a family based association sample of 270 Irish multiply affected families in whom the linkage had originally been found (5). Evidence for association was found with several SNPs and haplotypes (P=0.008–0.0001) in the vicinity of DTNBP1, although no specific susceptibility variants were identified. Replication rapidly followed in another family based study of 78 German and Israeli families (also showing evidence for linkage to 6p), and 127 proband–parent trios, mainly from Germany but including a small number of subjects from Hungary (16). Both samples independently gave evidence for association, with the combined datasets giving strong evidence (P=0.00001) for a three-marker haplotype.
Disappointingly, a second study based upon 219 Irish cases and 231 controls initially failed to find evidence for association (17), as did our own large case–control study of 708 cases and 711 controls. However, we went on to screen all the known and predicted exons as well as four putative alternative DTNBP1 promoters for sequence variation. When novel SNPs, particularly one from the most 5' promoter were included with markers from the original study, highly significant evidence for association was obtained (minimum global P=0.00005) (18). When the same markers were examined in the Dublin sample that was previously negative (17), the specific risk haplotype was again significantly more common in the patient sample (P=0.017) (unpublished data).
Taken together, the data from five samples studied by three independent groups provide compelling evidence that DTNBP1 is a susceptibility gene for schizophrenia. However, individual SNPs or haplotypes that directly increase disease susceptibility have not yet been found. The Cardiff and Dublin samples have identical risk haplotypes, but these differ from those in the other studies (16,18). It seems likely that the differences reflect allelic heterogeneity at the DTNBP1 locus (16). Our direct gene analysis suggests it is unlikely that susceptibility is conferred by non-synonymous variation, but there is evidence in the general population for cis-acting variants that alter DTNBP1 expression in human brain (19). These are clearly prime candidates for being the true susceptibility variants, but so far are unidentified.
The function of dysbindin is uncertain. It binds to ß-dystrobrevin in the CNS, and is thought to be a component of the dystrophin protein complex (20) found in postsynaptic densities (21). It may therefore play a role in synaptic structure and function in the brain (15), but this is entirely speculative.
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NEUREGULIN 1 (NRG1) |
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The deCODE Genetics group identified several risk haplotypes for schizophrenia around neuregulin 1 (NRG1) after performing systematic LD analysis across a linkage region they, and others (Table 1), had identified on 8p (22). Each haplotype shared a core risk haplotype (P=0.000087–0.0000067, OR=2.1) (22). deCODE subsequently replicated the specific risk haplotype in a large Scottish sample (P=0.00031) (23), as did we in a somewhat larger sample (P=0.04) (24). In our sample, the OR was smaller than others reported (1.25), but larger in cases with an affected first degree relative (OR=1.65, P=0.019).
These studies strongly suggest NRG1 is a gene for schizophrenia. The specific risk alelles and pathogeneic mechanisms are unknown. It has been proposed that NRG1 might influence disease susceptibility by altering the expression and activities of a broad range of neuroreceptors, particular NMDA glutamatergic receptors (23). NRG1 is also an important regulator of glial cells and myelination (25–27). Given the considerable body of evidence implicating white matter abnormalities in schizophrenia (28), an alternative hypothesis is that altered NRG1 function results in abnormal myelination. Yet another hypothesis, extensively outlined elsewhere, is that altered NRG1 leads to a functional deficiency of glia, and that this results in synaptic destabilisation (29).
As an interesting footnote to the NRG1 story, the most striking finding from one of the few published global expression profiling studies of schziophrenia was that six genes, all strongly expressed in oligodendrocytes and implicated in the formation of myelin sheaths, were downregulated in the post mortem brains of schizophrenics (30). Surprisingly, given the obvious challenges and artefacts involved in studies of post mortem brain, many of these changes have been independently replicated (28), One of the genes, ERBB3, belongs to a family of neuregulin receptors. The subsequent implication of NRG1 in schizophrenia provides striking evidence that even in the most difficult tissue of all (human brain) and in one of the most difficult phenotypes (schizophrenia), global expression studies can identify aetiologically relevant pathways (and see also RGS4 below).
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G30, G72 AND D-AMINO ACID OXIDASE |
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The third schizophrenia gene to be claimed by positional genetics was identified by Chumakov et al. (31) who obtained a strong LD signal from haplotypes (P=3x10-6 after correcting for multiple testing) within a 5 Mb candidate region of 13q22–34. The signal localised around two overlapping genes, G30 and G72, located on opposite DNA strands. There are no known homologues for either, nor did analysis of putative ORFs reveal likely function. Both were expressed in brain but only G72 gave a in vitro translation product, designated PLG72. Analysis of PLG72 in the yeast 2-hybrid system revealed interaction with D-amino acid oxidase (DAO, DAAO). Remarkably, Chumakov et al. (31) were able to demonstrate that DAO was also associated with schizophrenia (P=0.001).
The function of DAO is largely unknown, but it may be a detoxifying enzyme (32). It also appears to modulate D-serine, which is an endogenous modulator of NMDA glutamatergic receptors (33). Chumakov et al. (31) therefore speculated that the G72/DAO associations support the long-standing hypothesis of abnormal glutamatergic transmission in schizophrenia.
The statistical evidence for association between G72/G30 and schizophrenia is impressive, as is the additional finding of association with the interacting gene DAO. However, there are no, as yet, published independent replications. In the same manuscript (31), the authors reported evidence for single marker association in the region of G72/G30 in a Russian sample of just less than 200 cases and controls, but surprisingly did not report the results of haplotype analysis, or of DAO genotyping, in that sample. Recently, encouraging data have been reported regarding the G72/G30 complex in Bipolar Disorder (BPD) (34) in two samples. If the associations in both BPD and schizophrenia are replicated, it will have important ramifications for the classification of major psychiatric disorders.
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LOCALISATION OF GENES BY CHROMOSOMAL ABNORMALITY |
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There are many reports of associations between schizophrenia and chromosomal abnormalities (35–37) but for only two is the support convincing. A (1;11)(q42;q14.3) balanced reciprocal translocation was found to co-segregate with schizophrenia (LOD 3.6) and other psychiatric disorders (LOD 7.1) (38). The translocation site on chromosome 1 is near the markers implicated in two Finnish linkage studies (39,40), and disrupts three genes of unknown function (41). The pathogenic mechanisms in this family remain unknown, and until mutations or associations have been identified in other samples (42), or convincing biological evidence implicating this locus in schizophrenia has been obtained, it is uncertain whether the disease mechanisms related to this translocation are of wider relevance.
The second abnormality is the association between Velo–Cardio–Facial syndrome (VCFS) and schizophrenia. VCFS is associated with small interstitial deletions of chromosome 22q11. Its phenotype is variable, but includes a dramatic increase (about 20–30-fold) in the risk of psychosis especially schizophrenia (43–46). This raises the possibility that there is a gene within the VCFS deleted region that is involved in susceptibility to schizophrenia in cases without a deletion. Some support for this is provided by the schizophrenia linkage studies implicating 22q (Table 1), the emergence of 22q11 as a region of interest in the meta-analysis of Lewis and colleagues (13), and the observation that mice heterozygously deleted for some of the VCFS deletion orthologs have sensorimotor gating and memory impairments reminiscent of those seen in schizophrenics (47). As we discuss below, the VCFS region has therefore continued to be a focus of interest.
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ASSOCIATION STUDIES OF FUNCTIONAL CANDIDATE GENES |
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It is impossible for us to present the results of the myriad candidate gene analyses of schizophrenia that have been reported. Instead, we will focus on some of the novel findings for which there is at least some replicated support or which are, for other reasons, of particular interest. We start with a brief mention of two old findings, DRD3 and HTR2A. These have been extensively investigated and almost as extensively reviewed (48).
The dominant neurochemical hypotheses of schizophrenia involves dysregulation of the dopaminergic system and more recently the serotonergic system. These hypotheses have received some support from genetics, with reports of association between schizophrenia and homozygosity for a Ser9Gly polymorphism in exon 1 of the gene encoding the dopamine D3 receptor (49), and between a synonymous T102C polymorphism in the gene encoding the 5HT2a receptor (50,51). Positive and negative reports have followed but recent meta-analysis (52) of 48 DRD3 and 28 HTR2A studies suggests that both associations are true positives. Although the effect sizes are very small (OR1.1), their importance is that they suggest the neurochemical hypotheses are at least partly correct. Meta-analysis notwithstanding, the findings will only prove convincing if functionally important variants in these genes are uncovered, and associated with disease status. So far, there are no convincing data for any functionally important polymorphism in either gene, nor for HTR2A are there even moderately common cis-acting polymorphisms that alter mRNA abundance in adult brain (19).
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RGS4 |
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Genetic studies of RGS4 (regulator of G protein signalling-4) (53) were initiated after down-regulation of RGS4 mRNA was found in the brains of schizophrenic patients (54,55). RGS proteins act to dampen the effects of agonists at G protein coupled receptors (GPCRs) and given the postulated overactivity at dopamine and serotonin receptors in schizophrenia, this finding appeared to be plausibly related to schizophrenia pathogenesis. Moreover, RGS4 maps to 1q21–q22 a region implicated in schizophrenia by linkage (Table 1).
Chowdari et al. (53) investigated two proband–parent trio samples from the US and from India, as well as a third small sample recruited by the NIMH Collaborative Genetics Initiative. Significant associations were independently obtained in each of the US samples for haplotypes encompassing four SNPs in the 5' flanking sequence and first intron of RGS4. As for DTNBP1, different alleles in different samples defined the risk haplotype. Significant association was not obtained for the larger Indian sample, but the overall evidence for association was significant across all three samples (P=0.0027). We were able to replicate the evidence for two of the SNPs that had previously been individually associated. Moreover, we were able to replicate association with two marker haplotypes (unpublished data). Although three samples have now shown independently significant evidence in favour of association, the cumulative evidence for RGS4 as a susceptibility gene for schizophrenia is still modest, and further replication studies are urgently required.
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COMT |
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Catechol-O-methyl transferase (COMT) is a candidate gene for schizophrenia not only because it encodes a key dopamine catabolic enzyme but also because it maps to the VCFS region. The COMT protein occurs as two distinct forms: a soluble form found in the cell cytoplasm (S-COMT) and a longer, membrane-bound form (MB-COMT). In most assayed tissues, the S-COMT form predominates, accounting for
95% of total COMT activity (56,57). However, the MB-COMT form is the more prevalent species in brain (58). The COMT gene contains a valine-to-methionine (Val/Met) substitution at codon 108 and 158 in the S-COMT and MB-COMT transcripts, respectively (59). The Val form of S-COMT is reported to have higher activity and thermostability than the Met (59,60). The effect on MB-COMT is unknown. There is weak and inconsistent evidence that the Val variant may be associated with increased risk of schizophrenia. Most case–control studies (61–63) and meta-analysis (52) do not support association whereas studies employing a family design have (64–66). The Valine allele has been more reliably associated with reduced performance in tests of frontal lobe function (66,67), providing a possible mechanism by which COMT might act as a susceptibility or modifying locus for schizophrenia.
Recently, Shifman et al. (68) reported a large study of COMT in schizophrenia, including over 700 patients and 4000 controls. Despite the very large sample, the evidence for association with the Val/Met polymorphism was modest (P=0.024) whereas two other polymorphisms (intron 1 and 3' flanking region) were highly significantly associated, as was the haplotype of all three markers (P=9.6x10-8, OR=1.46).
This finding, though statistically impressive, is so far unreplicated. Our own sample, which has power greater than 0.95 to replicate, shows no evidence for association with any of the three SNPs or the haplotype (unpublished data). The study of Shifman et al. (68) was performed upon a sample of Ashkenazi Jews on the premise that they are relatively homogeneous for genetic (and environmental) risk factors. If this premise is correct, differences in the genetic architecture of other samples will make interpretation of negative data like our own difficult.
The findings of Shifman suggest that if COMT is associated with schizophrenia, it is not attributable to the Val/Met polymorphism. Given that COMT degrades dopamine, that most treatments for schizophrenia block dopaminergic transmission while psychotogenic drugs enhance it, and that deletion of 22q11, including COMT, is associated with schizophrenia, Bray et al. (69) postulated it is more plausible that the haplotype associated with schizophrenia is associated with low COMT expression rather than with high activity. They were able to show that the COMT haplotype implicated in schizophrenia (68) is indeed associated with lower expression of COMT mRNA, and that the 3' flanking region SNP giving strongest evidence for association with schizophrenia (68) is actually transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Their results support the hypothesis that the haplotype implicated in schizophrenia susceptibility may exert its effect, directly or indirectly, by down-regulating COMT expression. The importance of this for schizophrenia biology is that the findings are compatible with the classic hyper-dopaminergic theory of schizophrenia. They also suggest that reduced expression of COMT by virtue of its deletion might underlie the increased risk of schizophrenia seen in VCFS.
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PRODH |
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Liu et al. (70) reported a complex pattern of associations between schizophrenia and SNPs, haplotypes, and mis-sense substitutions in the PRODH (proline dehydrogenase) gene. PRODH was studied for two reasons. First, it is located in the VCFS region. Second, mice with an inactivated PRODH gene have abnormalities of sensorimotor gating similar to those in humans that some consider a trait marker for schizophrenia (71). The associated haplotype and the mis-sense substitutions in exon 12 appeared to act independently as risk factors for schizophrenia, and association was more pronounced in juvenile onset schizophrenia or when the onset was in childhood.
The first published replication attempt was negative (72). However, this was very limited in scope in that only the most significant SNP from Liu et al. (70) was tested in a rather small sample of Chinese parent–proband trios. We have examined PRODH in more detail using our case–control sample, a sample of VCFS probands with and without schizophrenia, and a sample of 55 proband–parent trios with juvenile onset schizophrenia. Despite each sample having >95% power to replicate the findings, in none did we find evidence for association between either the putative PRODH risk haplotype or the mis-sense substitutions (73,74). Given the high power to replicate the previous findings, our data suggest the previous association was due to chance.
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CONCLUSIONS |
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Schizophrenia is at last yielding its secrets to molecular genetic investigation, but until the susceptibility variants and pathogenic mechanisms are identified, there is room for caution. Nevertheless, in our view, the evidence now strongly implicates DTNBP1 and NRG1 as susceptibility loci, although in the case of NRG1, we note that there has only been a single fully independent replication. The priorities are now to isolate the susceptibility variants or haplotypes, to investigate their relationships with the phenotype, to examine the possibility of genetic and functional interactions between these and the other putative loci and to investigate the normal and abnormal biology of the gene products. The evidence for COMT, RGS4, G30/G72 and DOA is promising but not yet compelling, but several groups now have samples that are large enough to have realistic prospects of replicating these findings if they are real and generally applicable across populations.
So far, the risk haplotypes appear to be associated with small effect sizes (OR<2.5) and do not fully explain the linkage findings that prompted each study. These observations could suggest that the associated polymorphisms/haplotypes are only in weak LD with the true pathogenic variants. It is also possible that the linkages reflect variation at two or more genes.
The existence of several other promising linkages (Table 1) suggests that other susceptibility genes for schizophrenia are likely to be found in the coming years and the imperative here must be to undertake detailed mapping studies. As for other phenotypes, success has been achieved in the absence of fully robust and entirely persuasive linkage evidence (22). Initial gene localisation (rather than precise risk haplotype delineation) has been achieved, as again for all other positionally cloned phenotypes, without regard to haplotype block structures and with considerably lower marker densities than are generally required to extract even the common haplotype information. Moreover, although in the future, it may prove that the current crop represent ‘low lying fruit’, as for other disorders, localisation has been achieved in samples which are far smaller than the sample sizes of many thousands that some have feared will be required. Replication in unlinked samples, or identification of susceptibility loci in the absence of linkage may, however, be a different matter.
Another important lesson specifically for schizophrenia researchers is that linkage and gene identification in every case has been achieved by exploiting classical clinical phenotypes. This is not to say that when valid, and hopefully genetically less complex, endophenotypes are available, the task will not be easier. However, in the meantime, we should now acknowledge that the schizophrenia phenotype is of proven utility.
The ability of positional genetics to implicate novel genes and pathways in the pathogenesis of schizophrenia has already opened up new vistas for neurobiological research (75) and we can expect more in the coming years. Genetic studies are now poised to deliver crucial insights into the nature of schizophrenia.
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ACKNOWLEDGEMENTS |
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We are grateful to the MRC who support most of our research into schizophrenia via a Programme grant. We are also grateful to the Wellcome Trust and to NIMH for their project grant support.
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +44 2920743058; Fax: +44 2920746554; Email: owenmj{at}cf.ac.uk
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