In the last two years, whole genome association (WGA) studies have identified new candidate genes for several complex diseases, including age-related macular degeneration, diabetes, inflammatory bowel disease, and myocardial infarction. Initial reports have now been published in Molecular Psychiatry for schizophrenia (Lencz et al., 2007) and bipolar disorder (Baum et al., 2007), and several national and international consortia are currently planning or performing very large-scale studies in both disorders. Thus, it is timely to begin considering the potential implications of these investigations.

In their current paper, Baum et al. (2007) present data consistent with a polygenic, common disease/common variant model. No genetic variants of large effect were detected, although the authors duly note that the limitations of the current generation of microarray technology, as well as their pooling approach to genotyping, make a definitive statement premature. For example, the Illumina platform utilized in this study does not cover the pseudoautosomal region that we identified...  Read more

View all comments by Todd Lencz

This paper describes a large, well-conducted, two-stage genetic association study of bipolar disorder using a DNA pooling approach. A genome-wide set of over 500,000 SNPs (Illumina platform) was used in a U.S. discovery sample of 460 cases and 560 controls and 1,877 SNPs were taken forward into a pooling replication experiment in a German sample of 772 cases and 876 controls. The 88 SNPs showing evidence for association in the same direction in both the U.S. and German pools were then typed individually in all the samples. Four SNPs showed combined evidence for association at p This study demonstrates the potential utility of genome-wide association approaches and points to several loci that may influence susceptibility to bipolar disorder. Because of the modest effect sizes of the loci and the oligogenic/polygenic nature of mood and psychotic illness it will be crucial for the reproducibility and generalizability of such findings to be tested...  Read more

View all comments by Nick Craddock

This paper reports the results of a genome-wide association study of seven common diseases—including bipolar disorder—carried out by the Wellcome Trust Case Control Consortium (WTCCC). Although it comes at the end of a recent wave (tsunami?) of papers reporting genome-wide association results, this important work deserves careful study. Aficionados will appreciate the rich methodological detail and the careful approach to many issues—population stratification, the relationship of SNPs to genes, correction for multiple testing—that worry those of us who do these studies. Everyone will get a sense of the power of this new approach to detect genetic signals that have long eluded the best efforts of the field.

Although it returned fewer highly significant “hits” than most of the other diseases, the bipolar disorder sample (ably collected and phenotyped by Craddock and colleagues) nevertheless yielded many interesting findings. These are worthy of follow-up either by virtue of their statistical significance, apparent biological plausibility, or...  Read more

View all comments by Francis McMahon

I would caution that G72 has not been shown to be an actual gene, and in the four years since Chumakov and colleagues' report, the biochemistry has not been reproduced.

View all comments by Edward Scolnick

Reply to comment by Dr Scolnick
We agree that caution is required regarding the assumption that the genetic association at this locus is causally related to the DAOA "gene," and this is the reason that in the paper we have referred to the "DAOA/ G30 locus." Establishing robust genetic association in a restricted region of the genome is clearly the first step on a path to characterizing the biological and phenotypic relationships associated with the variation. It is entirely possible that pathologically relevant variation occurs at the DAOA/G30 locus that does not involve a protein product of the DAOA DNA sequence.

View all comments by Nick Craddock
View all comments by Michael Owen

The DAOA/G30 locus is a paradigm of association in psychiatric genetics, where positive reports are followed by both confirmation of association and failures to associate, with the observers of the glass being half-full commenting that it is unlikely that replication would occur spuriously multiple times, and those seeing the glass as half-empty (or three-quarters empty) emphasizing allelic inconsistencies, lack of identified causative SNPs, and in the case of DAOA/G30, lack of conclusive evidence of a gene expressed in brain. Clearly, we are just scratching the surface of understanding the reasons for any association signal in this region of the genome. It is important to remember that the DAOA/G30 locus was cloned from a region that has shown linkage in a number of studies, giving prior probability to association analyses, and that association has been reported in samples from a number of corners of the world. Expression may be restricted to discrete times in development and may not be present in abundance in middle-aged brains. It is also possible, as noted by Mike Owen,...  Read more

View all comments by Daniel Weinberger

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary Reid

Terrific update and summary for those of us not attending the meeting.

View all comments by William Carpenter

The work by Ferreira et al. exemplifies the growing enthusiasm for collaborative work among investigators and marks the new era of collaborative genetic research in complex disorders. The LD data found in the extant HapMap SNPs allow investigators to use sophisticated computational approaches to impute genotypes based on these HapMap data sets and the data generated from the experimental sample, thereby maximizing the utility of the actual genotyping itself. Nothing short of brilliant. Correlates between imputed and true genotypes were estimated to be 0.987, which is quite good. The significance estimates of the combined data analyses of the three data sets identifies two genes (ANK3 and CACNA1C) in the genomewide significance range with a p value of 10^-8, which is most reassuring and even more so considering that the CACNA1C gene was identified previously. The humbling fact in the mix is that the odds ratios are modest, ranging from 1.2 to 1.4, which is nonetheless in a similar arena as other complex genetic disorders such as diabetes. It is further humbling (and...  Read more

View all comments by Melvin G. McInnis

Ferreira et al. propose two specific genes to be related to bipolar disorder, ANK3, which is indirectly related to sodium channels, and CACNA1C, which is a calcium channel subunit. They hypothesize that bipolar disorder is, at least in part, a channelopathy. This hypothesis is consistent with a number of physiological observations made over the past several decades, as reviewed elsewhere.

The genetic data these authors present is certainly suggestive. They have analyzed three independent data sets, STEP-UCL (Sklar et al., 2008), Wellcome Trust (Wellcome Trust Case Control Consortium, 2007), and a third set called ED-DUB-STEP2 (not yet published). Their total sample exceeds 4,000 cases and 6,000 controls. They have direct genotype data on >300,000 SNPs and have imputed nearly 1.5 million additional. Their highest significance values (10^-7 to 10^-9) include a combination of genotyped and imputed SNPs. For each of these, the combined p value is a product of...  Read more

View all comments by John I. Nurnberger, Jr.

Are we there yet? Have we in the field of bipolar genetics finally been delivered to the promised land by GWAS? For the past year or so since GWAS burst on the scene, we have had to watch with envy as an impressive list of genes were convincingly implicated in a range of other complex diseases like type 2 diabetes, the apparent poster child for GWAS. Now, is it our turn?

The first attempts at individual-level GWAS of bipolar disorder by WTCCC and STEP-UCL were exciting because of their novelty, but the results were not particularly overwhelming. None of the findings withstood correction for the massive multiple testing inherent in GWAS, and those at the top were of ambiguous relevance to bipolar disorder. Confronted with such uninspiring findings, one could not be faulted for experiencing pangs of doubt that maybe for psychiatric disorders, GWAS would prove no better than its dusty old predecessor, the genomewide linkage study, in illuminating the underlying genetic architecture.

Nevertheless, encouraged by the lessons learned from GWAS of type 2 diabetes that the...  Read more

View all comments by Peter P. Zandi

The three companion papers published in Nature provide important new evidence for a role of the MHC complex and common variation across the genome in risk for schizophrenia. These studies have exploited the availability of comprehensive genotyping technologies, coupled with large cohorts of cases and controls, to identify candidate loci for disease susceptibility.

A notable feature of these papers is the clear willingness of each of the groups to share its data, and to provide overlapping presentations of each others’ results. The combination of datasets permitted the statistical significance of the MHC findings to emerge, thereby increasing confidence in results. The implication that immune processes may interact with genetic risk to influence schizophrenia risk is consistent with several lines of evidence, including our own small GWAS study (Lencz et al., 2007) implicating cytokine receptors in schizophrenia susceptibility.

Perhaps most intriguing is the finding from the International Schizophrenia Consortium demonstrating that a “score” test—combining...  Read more

View all comments by Todd Lencz
View all comments by Anil Malhotra

The three Nature papers reporting GWAS results in a large sample of cases of schizophrenia and controls from around Western Europe and the U.S. are decidedly disappointing to those expecting this strategy to yield conclusive evidence of common variants predicting risk for schizophrenia. Why has this extensive and very costly effort not produced more impressive results? There are likely to be many explanations for this, involving the usual refrains about clinical and genetic heterogeneity, diagnostic imprecision, and technical limitations in the SNP chips. But the likely, more fundamental problem in psychiatric genetics involves the biologic complexity of the conditions themselves, which renders them especially poorly suited to the standard GWAS strategy. The GWA analytic model assumes fixed, predictable relationships between genetic risk and illness, but simple relationships between genetic risk and complex pathophysiological mechanisms are unlikely. Many biologic functions show non-linear relationships, and depending on the biologic context, more of a potential pathogenic...  Read more

View all comments by Daniel Weinberger

The synthesis and extraction of the essence of the 3 Nature papers by Heimer and Farley represents science reporting at its best. Completion of the task while the ink was still wet shows that SRF is indeed in good hands. Congratulations on being concise, even-handed, non-judgmental, and challenging under the pressure of time.

View all comments by Irving Gottesman

Schizophrenia Genetics: Glass Half Full?
While it may be disappointing that the GWAS described above did not identify more genes, they nevertheless represent a landmark in psychiatric genetics and suggest a dual approach for the future: continued large-scale genetic association studies along with alternative genetic approaches leading to the discovery of new genetic etiologies, and more functional investigations to identify pathways of pathogenesis—which may themselves suggest new etiologies.

The consistent identification of an association with the MHC locus reinforces (without proving, as pointed out in the SRF news story) long-standing interest in the involvement of infectious or immune factors in schizophrenia pathogenesis (Yolken and Torrey, 2008). Epidemiologic and neuropathological studies that include patients selected for the presence or absence of immunologic genetic risk variants could potentially clarify etiology; cell and mouse model studies could clarify pathogenesis (  Read more

View all comments by Christopher Ross
View all comments by Russell L. Margolis

This report is unnecessarily negative, from my point of view. The three studies show not only that GWAS can identify susceptibility alleles for schizophrenia, but that the majority of risk comes from common variants of small effect. These can be found, but as in other complex traits and diseases, such as obesity and height, considerable power is needed, because effect sizes are small, meaning greater samples sizes. This approach works: there are now almost 60 variants influencing height (Hirschhorn et al., 2009; Soranzo et al., 2009; Sovio et al., 2009). Furthermore, the genes identified so far from both traditional mapping, CNV analysis and GWAS, point to two biological pathways, the integrity of the synapse (neurexin 1, neurogranin, etc.) and the wnt/GSK3β signaling pathway (DISC1, TCF4, etc.), which is involved in functions such as neurogenesis in the brain. The identification of disease pathways for schizophrenia has major...  Read more

View all comments by David Collier

Some commentators in their reflections take a rather negative view on what has been achieved through the application of GWAS technology to schizophrenia and psychiatric disorders more generally. We strongly disagree with this position. Below, we give examples of a number of statements that can be made about the aetiology of schizophrenia and bipolar disorder that could not be made at high levels of confidence even two years ago that are based upon evidence deriving from the application of GWAS.

1. We know with confidence that the role of rare copy number variants in schizophrenia is not limited to 22q11DS (VCFS) (reviewed recently in O’Donovan et al., 2009). We do not yet know how much of a contribution, but we know the identity of an increasing number of these. Most span multiple genes so it may prove problematic as it has in 22q11DS to identify the relevant molecular mechanisms. However, for one locus, the CNVs are limited to a single gene: Neurexin1 (Kirov et al., 2008;   Read more

View all comments by Michael O'Donovan
View all comments by Nick Craddock
View all comments by Michael Owen

GWAS Results: Is the Glass Half Full or 95 Percent Empty?
The publication of the latest schizophrenia GWAS papers represents the culmination of a tremendous amount of work and unprecedented cooperation among a large number of researchers, for which they should be applauded. In addition to the hope of finding new “schizophrenia genes,” GWAS have been described by some of the researchers involved as, more fundamentally, a stern test of the common variants hypothesis. Based on the meagre haul of common variants dredged up by these three studies and their forerunners, this hypothesis should clearly now be resoundingly rejected—at least in the form that suggests that there is a large, but not enormous, number of such variants, which individually have modest, but not minuscule, effects. There are no common variants of even modest effect.

However, Purcell and colleagues now argue for a model involving vast numbers of variants, each of almost negligible effect alone. The authors show that an aggregate score derived from the top 10-50 percent of a set of 74,000...  Read more

View all comments by Kevin J. Mitchell

Thumbs up or down on schizophrenia GWAS?
The triumvirate of schizophrenia GWAS studies just published in Nature gives cause for thought, and bears close scrutiny and reflection. To my reading, these three studies individually and collectively lead to an unambiguous conclusion—there is a lot of genetic heterogeneity and not one individual variant of common ancient origin accounts for a significant fraction of the genetic liability. To put it another way, there is no ApoE equivalent for schizophrenia. Strong past claims for ZNF804A and others look to have fallen by the statistical wayside. Putting the results of all three studies together does appear to provide support for a long known, pre-GWAS association with HLA, but otherwise it is hard to give a strong "thumbs up" to any specific result, not least because of the lack of replication between studies. The results are nevertheless important because the common disease, common variant model, on which GWAS are based and the associated cost justified, is strongly rejected as the main contributor to the genetic...  Read more

View all comments by David J. Porteous

The main question that arises from the three large genomewide association studies published in Nature is, What should we do next?

One important way forward would be to follow up the association findings in the MHC region. We need to understand the biological mechanism underlying this association. If the association signal is indeed related to infectious diseases, this line of inquiry may lead to the highly desired development of a treatment that might prevent the diseases in some cases.

One possible explanation for the association between schizophrenia and the MHC region (6p22.1) is that infection during pregnancy leads to disturbances of fetal brain development and increases the risk of schizophrenia later in life. A possible test for the theory of infectious diseases as risk factors for schizophrenia would be to study the associated SNPs in 6p22.1 in fathers and mothers of subjects with schizophrenia relative to parents of control subjects. If the 6p22.11 region is related to the tendency of mothers to be infected by viruses during pregnancy, we would expect the SNPs...  Read more

View all comments by Sagiv Shifman

The three companion papers in this week’s issue of Nature, in our view, support the case for investigating interaction between susceptibility genes and infectious exposures in schizophrenia. We and others have argued previously that genetic studies conducted in isolation from environmental factors, and studies of environmental influences in the absence of genetic data, are necessarily limited. Maternal influenza, rubella, toxoplasmosis, herpes simplex virus, and other infections have each been associated with an increased risk of schizophrenia, with effect sizes ranging from twofold to over fivefold. While these epidemiologic findings clearly require replication in independent cohorts, two new developments provide further support for the hypothesis. First, a growing number of animal studies of maternal immune activation have documented behavioral and brain phenotypes in offspring that are analogous to findings from clinical research in schizophrenia, and these findings are mediated in large part by specific cytokines (Meyer et al.,...  Read more

View all comments by Alan Brown
View all comments by Paul Patterson

Two hundred years after Darwin’s birth and 150 years after the publication of On the Origin of Species, these three papers in Nature show the important role of natural selection in shaping the genetic architecture of schizophrenia susceptibility. If we compare the GWAS results for schizophrenia with those obtained for other diseases, it seems that there are less common risk alleles and/or lower effect sizes in schizophrenia than in many other complex diseases (see, for instance, the online catalog of published GWAS at NHGRI). This fact strongly suggests that negative selection limits the spread of susceptibility alleles, as expected due to the decreased fertility of schizophrenic patients.

Interestingly, the MHC region may be an exception. This region represents a classical example of balancing selection, i.e., the presence of several variants at a locus maintained in a population by positive natural selection (Hughes and Nei, 1988). In the case of the MHC, this...  Read more

View all comments by Javier Costas