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Annotation

Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperaviciute D, Gennarelli M, Strittmatter WJ, Bonvicini C, Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RS, Fisher EM, St Jean PL, Giegling I, Hartmann AM, Möller HJ, Ruppert A, Fraser G, Crombie C, Middleton LT, St Clair D, Roses AD, Muglia P, Francks C, Rujescu D, Meltzer HY, Goldstein DB. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet . 2009 Feb 1 ; 5(2):e1000373. PubMed Abstract

Comments on Paper and Primary News
Primary News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  David J. Porteous, SRF Advisor
Submitted 11 February 2009 Posted 12 February 2009

The answer is unequivocally, “yes”
In co-highlighting the papers from Need et al., 2009, and Tomppo et al., 2009, you pose the question “CNV’s, interacting loci or both?” to which my immediate answer is an unequivocal “yes,” but it actually goes further than that. These two studies, interesting in their own rights, add just two more pieces of evidence now accumulated from case only, case-control, and family-based linkage on the genetic architecture of schizophrenia. Thus, we can reject with confidence a single evolutionary and genetic origin for schizophrenia. If it were so, it would have been found already by the plethora of genomewide studies now completed, studies specifically designed to detect causal variants, should they exist, which are both common to most if not all subjects and ancient in origin—the Common Disease, Common Variant (CDCV) hypothesis.

Moreover, for DISC1, NRG1, NRXN1, and a few others, the criteria for causality are met in some subjects, but none of these is the sole cause of schizophrenia. Their net contributions to individual and...  Read more


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Primary News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Pamela DeRosseAnil Malhotra (SRF Advisor)
Submitted 19 February 2009 Posted 22 February 2009

The results reported by Tomppo et al. and Need et al. collectively instantiate the complexities of the genetic architecture underlying risk for psychiatric illness. Paradoxically, however, while the results of Need et al. suggest that the answer to the complex question of risk genes for schizophrenia (SZ) may be found by searching a very select population for rare changes in genetic sequence, the results of Tomppo et al. suggest that the answer may be found by searching for common variants in large heterogeneous populations. So which is it? Is SZ the result of rare, novel genetic mutations or an accumulation of common ones? Such a conundrum is not a novel predicament in the process of scientific inquiry and such conundrums are often resolved by the reconciliation of both opposing views. Thus, if we allow history to serve as our guide it seems reasonable that the answer to the current question of what genetic mechanisms are responsible for SZ, is that SZ is caused by both rare and common variants.

Although considerable efforts, by our lab and others, are currently being...  Read more


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View all comments by Anil Malhotra

Primary News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 25 February 2009 Posted 25 February 2009

Has anyone considered the possibility that the CNVs found to be elevated in schizophrenia versus controls could be a peripheral effect and perhaps not present in brain tissue? For example, the diet of the typical schizophrenia patient is poor, and it is conceivable that chronic folate deficiency could predispose to problems in DNA structure or repair in lymphocytes. Thus, the CNVs could be an effect of the illness, and not a cause. Someone needs to do the experiment that compares CNVs in blood to those in the brain of the same individual. And then we need studies of the stability of CNVs over the lifetime of an individual.

View all comments by James L. Kennedy


Primary News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Kevin J. Mitchell
Submitted 2 March 2009 Posted 2 March 2009

The papers by Need et al. and Tomppo et al. seem to present conflicting evidence for the involvement of common or rare variants in the etiology of schizophrenia.

On the one hand, Need et al., in a very large and well-powered sample, find no evidence for involvement of any common SNPs or CNVs. Importantly, they show that while any one SNP with a small effect and modest allelic frequency might be missed by their analysis, the likelihood that all such putative SNPs would be missed is vanishingly small. They come to the reasonable conclusion that common variants are unlikely to play a major role in the etiology of schizophrenia, except under a highly specific and implausible genetic model. Does this sound the death knell for the common variants, polygenic model of schizophrenia? Yes and no. These and other empirical data are consistent with theoretical analyses which show that the currently popular purely polygenic model, without some gene(s) of large effect, cannot explain familial risk patterns (Hemminki et al., 2007;   Read more


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