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Annotation

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, . Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet . 2008 Sep ; 40(9):1053-5. PubMed Abstract

Comments on Paper and Primary News
Primary 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 (  Read more


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Primary 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...  Read more


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Comment by:  Timothy Crow
Submitted 18 December 2008 Posted 18 December 2008

O’Donovan and colleagues have conducted an intensive genomewide association study designed to isolate genes predisposing to schizophrenia. They conclude that of 12 loci with P <10(-5) deviations from expectation, three had strong independent support (P <5 x 10[-4]) in two replication studies. They argue that the relevance of this pattern of genes was emphasized by a meta-analysis, including bipolar disorder with a P equal to 9.96 x 10(-9).

While a very considerable amount of work and analysis has gone into this whole-genome survey, and this is to be welcomed, other interpretations and findings deserve consideration:

1. Although this group refer to a previous summary of the literature (Craddock et al., 2005) in which they concluded that a basket of genes (neuregulin, dysbindin, DISC1, G72, DAO, and others) were established as relevant to schizophrenia, no support for these genes was forthcoming from this study. This negative finding deserves note.

2. The strategy that O’Donovan et al. have adopted requires that genes...  Read more


View all comments by Timothy Crow

Comment by:  Michael O'Donovan, SRF AdvisorNick CraddockMichael Owen (SRF Advisor)
Submitted 6 January 2009 Posted 7 January 2009

Response to Comment by Tim Crow
Dr. Crow makes a few points concerning our recent genomewide association study (GWAS) of schizophrenia that he believes merit consideration. He draws attention to a reduction in the effect sizes we observed in the replication samples we used in our study in comparison to those we observed in our GWAS. As a related issue he notes that the P values are not obviously lower in the replication study than in the original study despite an increased sample size. This is factually correct. It is also expected when dealing with small effect sizes. It is well known that for true findings, initial studies will generally overestimate the effect sizes and that these will therefore subsequently drop in replication studies. This phenomenon is widely known as the winner's curse (see, e.g., Zollner and Pritchard, 2007). The reasons for the winner’s curse have been outlined elsewhere by many including ourselves (Craddock et al., 2008). Of course, it is also...  Read more


View all comments by Michael O'Donovan
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Comment by:  Timothy Crow
Submitted 27 January 2009 Posted 27 January 2009

I am grateful to Craddock et al. for a measured and thoughtful response to my comments and to SRF for providing a platform for discussion.

Craddock et al. concede that an increase in sample size by a factor of 10 did not lead to an increase in significance of the main finding of their whole-genome association study (O'Donovan et al., 2008). They invoke the “winner’s curse” (the scenario in which a genuine positive finding is followed by weaker or negative findings in attempts at replication) as the explanation. This seems to me risky logic. Science depends upon replication: if it’s not there, it’s not there.

These authors scrutinize their P values and pronounce that they have “strong replication evidence that would easily survive correction for multiple testing”…. I look at their table 2 and conclude they have identified the positive tail of the distribution of variation within the whole genome and are seeing its disappearance as the sample size is increased. My argument is that the gene they identify as related to...  Read more


View all comments by Timothy Crow
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