Schizophrenia Research Forum - A Catalyst for Creative Thinking


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 News and Primary Papers
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 (Porteous et al., 2006), in which the chromosomal translocation clearly segregates with disease, but in only one family. In addition, they are in general congruent with three other studies (Walsh et al., 2008; Kirov et al., 2008; Xu et al., 2008) which also demonstrate a role for copy number variation in schizophrenia. These studies together should put to rest many of the arguments about the value of genetics in psychiatry, so that future studies can now begin from a firmer base.

However, these studies also raise at least as many questions as they answer. One is the role of copy number variation in schizophrenia in the general population. The number of cases accounted for by the deletions on chromosome 1 and 15 in the ISC and Icelandic studies is extremely small--on the order of 1% or less. The extent to which copy number variation, including very rare or even private de novo variants, will account for the genetic risk for schizophrenia in the general population is still unknown. The ISC study indicated that there is a higher overall load of copy number variations in schizophrenia, broadly consistent with Walsh et al and Xu et al but backed up by a much larger sample size, allowing the results to achieve high statistical significance. The implications of these findings are still undeveloped,

Another issue is the relationship to the phenotype of schizophrenia in the general population. Many more genotype-phenotype studies will need to be done. It will be important to determine whether there is a higher rate of mental retardation in the schizophrenia in these studies than in other populations.

Another question is the relationship between these copy number variations (and other rare events) and the more common variants accounting for smaller increases in risk, as in the recent O’Donovan et al. (2008) association study in Nature Genetics. It is far too early to know, but there may well be some combination of rare mutations plus risk alleles that account for cases in the general population. This would then be highly reminiscent of Alzheimer’s disease, Parkinson’s disease, and other diseases which have been studied for a longer period of time.

For instance, in Alzheimer’s disease there are rare mutations in APP and presenilin, as well as copy number variation in APP, with duplications causing the accelerated Alzheimer’s disease seen in Down syndrome. These appear to interact with the risk allele in APOE, and possibly other risk alleles, and are part of a pathogenic pathway (Tanzi and Bertram, 2005). Similarly in Parkinson’s disease, rare mutations in α-synuclein, LRRK2 and other genes can be causative of PD, though notably the G2019S mutation in LRRK2 has incomplete penetrance. In addition, duplications or triplications of α-synuclein can cause familial PD, and altered expression due to promoter variants may contribute to risk. By contrast, deletions in Parkin cause an early onset Parkinsonian syndrome (Hardy et al., 2006). Finally, much of PD may be due to genetic risk factors or environmental causes that have not yet been identified. Further studies will likely lead to the elucidation of pathogenic pathways. These diseases can provide a paradigm for the study of schizophrenia and other psychiatric diseases. One difference is that the copy number variations in the neurodegenerative diseases are often increases in copies (as in APP and α-synuclein), consistent with gain of function mechanisms, while the schizophrenia associations were predominantly with deletions, suggesting loss of function mechanisms. The hope is that as genes are identified, they can be linked together in pathways, leading to understanding of the neurobiology of schizophrenia (Ross et al., 2006).

The key unanswered questions, of course, are what genes or other functional domains are deleted at the chromosome 1, 15, and 22 loci, whether the deletions at these loci are sufficient in themselves to cause schizophrenia, and, if sufficient, the extent to which the deletions are penetrant. Both of the current studies identified deletions large enough to include several genes. The hope is that at least a subset of copy number variations (unlike SNP associations identified in schizophrenia to date) may be causative, making the identification of the relevant genes or other functional domains—at least in principle—more feasible.

Another tantalizing observation is that the copy number variations associated with schizophrenia were defined by flanking repeat regions. This raises the question of the extent to which undetected smaller insertions, deletions or other copy number variations related to other repetitive motifs, such as long tandem repeats, may also be associated with schizophrenia. Identification and testing of these loci may prove a fruitful approach to finding additional genetic risk factors for schizophrenia.

References:

Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A. Genetics of Parkinson's disease and parkinsonism. Ann Neurol. 2006 Oct;60(4):389-98. Abstract

Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O'Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet . 2008 Feb 1 ; 17(3):458-65. Abstract

Porteous DJ, Thomson P, Brandon NJ, Millar JK. The genetics and biology of DISC1—an emerging role in psychosis and cognition. Biol Psychiatry. 2006 Jul 15;60(2):123-31. Abstract

Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006 Oct 5;52(1):139-53. Abstract

Singleton A, Myers A, Hardy J. The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R123-6. Abstract

Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell. 2005 Feb 25;120(4):545-55. Abstract

Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008 Apr 25;320(5875):539-43. Abstract

Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008 Jul;40(7):880-5. Abstract

View all comments by Christopher Ross
View all comments by Russell L. MargolisComment 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 more likely to be associated with cases lacking a family history is provocative but difficult to interpret as no data are given about the size of the families having a family history and those not having such a history. Unless these family samples are of comparable size and obtained by a comparable ascertainment strategy, it is hard to know how conclusive the finding is. Indeed, in the study of Walsh et al., rare CNVs were just as likely to be found in patients with a positive family history. Finally, in contrast to private CNVs, recurrent (but still rare) CNVs, such as those identified on 1q and 15q in the studies of the International Schizophrenia Consortium (Nature, 2008) and Stefansson et al. (Nature, 2008), are strongly implicated as being associated with the diagnosis of schizophrenia and therefore likely involved in the causation of the illnesses in the cases having these CNVs. In all, these new CNV regions, combined with the VCFS region on 22q, suggest that approximately five to 10 patients out of 1,000 who carry the diagnosis of schizophrenia may have a well-defined genetic lesion (i.e., a substantial deletion or duplication).

The overarching question now is how relevant these findings are to the other 99 percent of individuals with this diagnosis who do not have these recurrent CNVs. Before we had the capability to perform high-density DNA hybridization and SNP array analyses, chromosomal anomalies associated with the diagnosis of schizophrenia were identified using cytogenetic techniques. Indeed, VCFS, XXX, XXY (Kleinfelter’s syndrome), and XO (Turner syndrome) have been found with similarly increased frequency in cases with this diagnosis in a number of studies. Now that we have greater resolution to identify smaller structural anomalies, the list of congenital syndromes that increase the possibility that people will manifest symptoms that earn them this diagnosis appears to be growing rapidly. Are we finding causes for the form of schizophrenia that most psychiatrists see in their offices, or are we instead carving out a new set of rare congenital syndromes that share some clinical characteristics, as syphilis was carved out from the diagnosis of schizophrenia at the turn of the twentieth century? Is schizophrenia a primary expression of these anomalies or a secondary manifestation? VCFS is associated with schizophrenia-like phenomena but even more often with mild mental retardation, autism spectrum, and other psychiatric manifestations. The same is true of the aneuploidies that increase the probability of manifesting schizophrenia symptoms. The two new papers in Nature allude to the possibility that epilepsy and intellectual limitations may also be associated with these CNVs. The diagnostic potential of any of these new findings cannot be determined until the full spectrum of their clinical manifestations is clarified.

One of the important insights that might emerge from identification of these new CNV syndromes is the identification of candidate genes that may show association with schizophrenia based on SNPs in these regions. VCFS has been an important source of promising candidate genes with broader clinical relevance (e.g., PRODH, COMT). Stefansson et al. report, however, that none of the 319 SNPs in the CNV regions showed significant association with schizophrenia in quite a large sample of individuals not having deletions in these regions. The Consortium report also presumably has the results of SNP association testing in these regions in their large sample but did not report them. It is very important to explore in greater genetic detail these regions of the genome showing association with the diagnosis of schizophrenia in samples lacking these lesions and to fully characterize the clinical picture of individuals who have them. It is hoped that insights into the pathogenesis of symptoms related to this diagnosis will emerge from these additional studies.

Anyone who has worked in a public state hospital or chronic schizophrenia care facility (where I spent over 20 years) is not surprised to find an occasional patient with a rare congenital or acquired syndrome who expresses symptoms similar to those individuals also diagnosed with schizophrenia who do not have such rare syndromes. Our diagnostic procedures are not precise, and the symptoms that earn someone this diagnosis are not specific. Schizophrenia is not something someone has; it is a diagnosis someone is given. In an earlier comment for SRF on structural variations in the genome related to autism, I suggested that, “From a genetic point of view, autism is a syndrome that can be reached from many directions, along many paths. It is not likely that autism is any more of a discrete disease entity than say, blindness or mental retardation.” These new CNV syndromes manifesting schizophrenia phenomena are probably a reminder that the same is true of what we call schizophrenia.

View all comments by Daniel Weinberger

Primary Papers: Identification of loci associated with schizophrenia by genome-wide association and follow-up.

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 identified in Phase 1 be re-examined in the replication phases, and in this way those that are genuinely associated with disease are separated from those that are merely chance findings. Thus, the three genes that O’Donovan et al. select out should be distinct from those that they identify as chance findings.Table 1 (extracted from Table 2 of O’Donovan et al.) illustrates the problem.

Inspection of this table reveals that the odds ratios in the replication study are reduced relative to the initial study, and the P values, although they vary, are not obviously lower than in the original study. Therefore, it is unclear that an increase in sample size by a factor of 10 has led to any change in the P values observed. Importantly, there is not a clear discontinuity or distinction among the odds ratios for the three loci that O’Donovan et al. emphasize (the first three in Table 1) and those that they regard as probably chance findings. Both show a scatter of P values not obviously decreased, and regression to the mean of the odds ratio.

3. Findings with respect to these gene loci were not replicated in another genomewide association study of schizophrenia (Lencz et al., 2007). Although the authors emphasize a relationship to bipolar disorder, these loci were not shown to be associated in the recent study of Sklar et al. (2008).

These considerations emphasize the fragility of whole-genome analysis as an approach to genes predisposing to psychosis, and the salient absence of replicated findings in the field.

References:

Craddock N, O’Donovan MC, Owen MJ. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet. 2005;42:193-204. Abstract

Lencz T, Morgan T, Athanasiou M, Dain B, Reeds CR, Kane JM, Kucherlapati R, Malhotra AK. Converging evidence for a Pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry. 2007;12:572-80. Abstract

Sklar P, Smoller JW, Fan J, Ferreira MAR, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Farone SV, Kirby A, de Bakker PIW, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D, Scolnick EM, Daly MJ, Blackwood DH, Gurling HM, Purcell SM. Whole-genome association study of bipolar disorder. Mol Psychiatry. 2008;13:558-69. Abstract

View all comments by Timothy Crow

Primary Papers: Identification of loci associated with schizophrenia by genome-wide association and follow-up.

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 true that effect sizes will also drop for false positives taken forward, so it is reasonable to require significant replication before a finding can be accepted as true. In our paper, for a number of loci, we obtained strong replication evidence that would easily survive correction for multiple testing, but for no single locus did we consider the evidence to be sufficient to allow us to say the evidence was unequivocal. We did find, however, that the distribution of independent replication signals we obtained in our follow-up sample was extremely unlikely (p = 9x10-8) to have occurred with a random set of SNPs. So improbable is that finding under the null hypothesis that this seems to us compelling evidence that one or more of the loci we highlight represents a true susceptibility locus. If Dr. Crow has a more credible alternative explanation, we would be very keen to hear it.

In addition to the above, Dr. Crow makes familiar points relating to cross-study replication. Replication is, of course, the gold standard; that is why we sought (and obtained) it using much larger and more powerful samples than have been used to date in schizophrenia genetics. When assessing failures to replicate, Dr. Crow entirely ignores power issues, which are so vital when trying to infer evidence for an absence of effect from absence of evidence for an effect. For example, in the earlier GWAS study of Lencz and colleagues (Lencz et al., 2007), that study had power of less than 10 percent to detect an association to the strongest finding we reported (ZNF804A) at p = 0.05, and power of less than one-thousandth of 1 percent to detect the ZNF804A finding at a threshold similar to that which we obtained in our GWAS.

While we certainly accept that our GWAS study does not provide definitive evidence for (or, for power reasons, against) any specific gene, our study is properly interpreted as providing compelling evidence for the existence of some common risk alleles of small effect in schizophrenia and that some of the loci we have highlighted represent true susceptibility alleles. We also consider that our promising findings point to the likely success of the GWAS approach as datasets expand in power in the coming years. In saying so, we certainly do not think GWAS studies are a panacea, nor do we think they will uncover the entirety of the genetic architecture of schizophrenia, which may include effects too small and/or too rare to be detectable by GWAS in realistic samples. We are not entirely sure what Dr. Crow means by ”the fragility of whole-genome analysis as an approach to genes predisposing to psychosis,” but if he has any novel ideas about methods which come with a guarantee for identifying common risk alleles with small effects, we and the whole field of human genetics would no doubt be delighted to hear them.

References:

Zollner S, Pritchard JK. Overcoming the winner's curse: estimating penetrance parameters from case-control data. Am J Hum Genet. 2007 Apr 1;80(4):605-15. Abstract

Craddock N, O'Donovan MC, Owen MJ. Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry. 2008 Jul 1;13(7):649-53. Abstract

Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM, Kucherlapati R, Malhotra AK. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry. 2007 Jun 1;12(6):572-80. Abstract

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

Primary Papers: Identification of loci associated with schizophrenia by genome-wide association and follow-up.

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 schizophrenia is not distinguished from the set of other genes selected by statistical association in the replication procedure. I agree it is interesting that the P value decreases when a bipolar sample is added, but this was not the primary analysis, and the fact is that the independent study of Sklar et al. (2008) of bipolar disorder did not identify anything at this locus. In this multivariate literature we can all recollect alluring P values that subsequently melted away!

Craddock et al. are right to point out that their core study was larger than that of Lencz et al. (2007) by a factor of 1.37 for schizophrenia probands and 20 for the control population. Statistical power indeed is important. The point has force in the reverse comparison, i.e., of Lencz et al. with the Wellcome sample. The single positive finding (in the pseudo-autosomal region) in Lencz et al. was not confirmed in the Wellcome sample, and therefore cannot be regarded as replicated.

Craddock et al. question my phrase “the fragility of whole-genome analysis as an approach.” What I should have said was “fragility of the findings of whole-genome analysis....” With civility they then ask if I have “any novel ideas about methods which come with a guarantee for identifying…” what they describe as common “risk alleles with small effects...” for which I substitute...“the genetic predisposition to psychosis.” My response to their invitation is that the possibility should not be excluded that the variation we all seek lies not in the sequence, but in a modification of the histone structure with which the sequence is associated in the chromosome. These authors will be bored to hear me repeat that the transition from a prior species to modern Homo sapiens and its associated variation is the critical genetic event we have to identify, but the case is on record (Crow, 2008; Williams et al., 2006).

This brings me to the point in my commentary that Craddock et al. have overlooked, and of which I would very much like to hear their opinion—that the findings in the Wellcome Trust samples that they report have a bearing on the set of “candidate genes” that are so prominent in the current literature. Is it not the case that if there is really significant sequence variation associating schizophrenia with dysbindin, neuregulin, DISC1, etc., and such variation is transmitted through generations, it should have been detected in the study they report? Is not the fact that it is not seen significant? Why was it not seen either in their study or in other association studies (Sanders et al., 2008)? These studies are sufficiently powered to detect variation of the size implicated by the original positive linkage studies (though the linkage findings were generally not supported by systematic sibling pair studies—Crow [2007]). Do we not have here a critical test of the type that Medawar (1969) and other philosophers of science would urge us to seek, and a decisive refutation of the basket of hypotheses associated with candidate genes?

If so, then a robust statement to this effect from the Cardiff group (who have been sanguine about the candidate genes in their reviews) would have a salutary effect on the field. It would signal the elimination of hypotheses that have been widely discussed, and therefore would indicate progress. It would recognize the possibility that unearthing the genetic predisposition to psychosis is a more difficult task than any of us have thought.

References:

Crow TJ. How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry. 2007 Jan 1;164(1):13-21. Abstract

Crow TJ. The 'big bang' theory of the origin of psychosis and the faculty of language. Schizophr Res. 2008 Jul 1;102(1-3):31-52. Abstract

Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM, Kucherlapati R, Malhotra AK. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry. 2007 Jun 1;12(6):572-80. Abstract

Medawar, P.B. (1969), Induction and Intuition in Scientific Thought Methuen, London.

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 1;40(9):1053-5. Abstract

Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, Burrell GJ, Rice JP, Nertney DA, Olincy A, Rozic P, Vinogradov S, Buccola NG, Mowry BJ, Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Crowe RR, Cloninger CR, Martinez M, Gejman PV. No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry. 2008 Apr 1;165(4):497-506. Abstract

Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, de Bakker PI, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D, Scolnick EM, Daly MJ, Blackwood DH, Gurling HM, Purcell SM. Whole-genome association study of bipolar disorder. Mol Psychiatry. 2008 Jun 1;13(6):558-69. Abstract

Williams NA, Close JP, Giouzeli M, Crow TJ. Accelerated evolution of Protocadherin11X/Y: a candidate gene-pair for cerebral asymmetry and language. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):623-33. Abstract

View all comments by Timothy Crow