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Genome Yields Clues to Biology of Childhood Brain Disorders

The National Association of Science Writers (NASW) and the Council for the Advancement of Science Writing (CASW) held annual meetings together 5-9 November 2010 at Yale University in New Haven, Connecticut. SRF writer Pete Farley helped put together the joint event—ScienceWriters 2010—which marked NASW's seventy-fifth and CASW's fiftieth anniversaries. Victoria Wilcox sends in this report on a special lecture from the meeting.

20 December 2010. High-speed genomic techniques are ushering in an era of relatively consistent findings that could lead to treatment targets for childhood neuropsychiatric disorders, according to Matthew State of Yale University, New Haven, Connecticut. In a lecture on 7 November, at the 2010 New Horizons in Science briefing in New Haven, sponsored by the Council for the Advancement of Science Writing, State described how these newer methods are facilitating the search for rare variants in particular and offer a shortcut to the underlying biology. For instance, his own work unexpectedly fingered a gene that affects levels of histamine in a unique family with Tourette’s syndrome. He has also tied divergent rare brain malformations in different people to mutations in a single gene, challenging beliefs that they involve separate pathways.

After the discovery of the Huntington’s disease gene, said State in a follow-up interview with SRF, the failure of the “one gene, one disease” model to yield similar results for other inherited neuropsychiatric disorders changed the paradigm. The new dogma, that these more complex disorders result from a “conspiracy” of common genetic variations led to efforts to identify the conspirators. Research groups would study their favorite gene and publish their findings, which were hardly ever replicated. “The enterprise became highly suspect because you’d have an association, and it would be one more publication cycle before someone would call that association into question,” State said in his lecture.

In the past three years or so, the availability of high-speed genomic technologies has improved the ability to find common variants of small effect; instead of choosing which genes to study, researchers could study the entire genome in an unbiased way without bankrupting the lab. Yet, State said, “We’ve seen more than 100 associations of common variations in the genome with a whole variety of medical disorders,” such as diabetes, aneurysms, and inflammatory bowel disease; “despite that, we still have not been able to find, as a general proposition, a single common variant in a child psychiatric disorder that has reproducibly been shown to be carrying risk for that disorder.” Taking a different approach, he and others have trained their periscopes on rare variants (see SRF related news story), in part because natural selection would probably limit the population frequency of mutations that cause illness.

A stake in the ground
In State's view, the rare variant approach “has very little to do with how much it explains in the population and everything to do with whether or not it can give you some novel insight into how to begin to treat these disorders.” Even findings that connect a lot of rare mutations to disease might point to a single functional network. One approach to identifying rare variants focuses on outliers, such as families who are inbred, show an extreme phenotype, or are very large. Among psychiatric genetics researchers, State noted to SRF, those who study schizophrenia were among the first to use this approach to explore biology, capitalizing on the discovery of the DISC1 mutation in the Scottish family (see SRF related news story). A second approach involves sequencing the entire coding part of the genome to find rare single-nucleotide variants. Until the recent development of high-throughput sequencing, the cost and difficulty of doing so forced researchers to focus on smaller parts of the genome, he said.

A door to the unexpected
State and colleagues have used the outlier approach to study Tourette’s syndrome, a genetic neurological disorder that causes children to repeatedly twitch, flap their arms, cough, squeak like a mouse, or engage in other semi-voluntary tics. First author A. Gulhan Ercan-Sencicek, also of Yale University, and others studied two generations of a family in which all eight children and the father, but not the mother or her side of the family, developed the syndrome. Unlike most families affected by Tourette’s, this one showed a pure Mendelian inheritance pattern.

As reported in the May 20 New England Journal of Medicine (Ercan-Sencicek et al., 2010), linkage analysis flagged one segment of chromosome 15. When the researchers sequenced the genes there, they found something surprising: a rare stop codon in the histidine decarboxylase, or HDC, gene in all affected but no unaffected family members. HDC makes the rate-limiting enzyme in histamine production. The team further showed that the mutant alters one side of a homodimer, decreasing histamine levels.

Previous research had found that HDC-knockout mice show tic-like behavior, which histamine reverses. Histamine acts throughout the brain, and in the striatum it blocks the release of dopamine, as do the antipsychotic drugs used to treat tics. State noted that drug companies first became interested in compounds that increase brain histamine for their potential as schizophrenia treatments. Because late-stage clinical trials are already testing some of these compounds as treatments for comorbid disorders related to Tourette’s syndrome, State thinks his rare variant finding might quickly lead to a clinical trial of a possible tic remedy.

Not so different after all
The new techniques enable researchers to use smaller pedigrees to hunt for variants over the genome. For instance, State and colleagues sequenced every exome in five inbred families from Turkey that would have been too small to study using older methods. In a paper published in Nature on September 9, first author Kaya Bilgüvar of Yale University and others (Bilgüvar et al., 2010) tied recessive mutations in WD repeat domain 62 (WDR62) to severe brain malformations in one family with two affected siblings, a finding supported in six other families. Although the mutations involved the same gene, they seem to have produced a range of phenotypes, such as microcephaly (small brain), pachygyria (cortical thickening), lissencephaly (smooth cortex), and others, which were previously thought to stem from distinct molecular mechanisms.

These results complement past work suggesting genetic overlap among different neuropsychiatric disorders. For instance, other studies have implicated duplications at 16p11.2 with increased risk for autism, schizophrenia, and other developmental abnormalities; deletions of that region to autism spectrum disorders and intellectual disability; and deletions in 22q11 to autism, velocardiofacial syndrome, and perhaps schizophrenia (see SRF related news story).

Opportunities in autism
About 20 years ago, State and colleagues identified an outlier group that they had no way to study genetically: children with childhood disintegrative disorder, an illness loosely within the autism spectrum. These youngsters develop normally for about two years and then regress, losing skills that they had previously acquired in areas such as language and social interaction. To determine whether de novo mutations play a role, the researchers are doing whole-exome and whole-genome sequencing and neuroimaging of these children and their families, a comprehensive approach made feasible by the new techniques. They hope the findings will not only help families affected by this rare illness, but also generate leads as to the biology behind social behavior in children.

The latest sequencing techniques are also helping researchers find rare variants in typical families instead of having to track down extreme phenotypes or pedigrees. State and colleagues are currently studying common-variety families that include one child with autism. So far, he told SRF, they are finding “a lot of rare variation in the genome; there are many, many things in the genome that we’ve never seen before because we haven’t had the ability to see them.” Before they publish the results, he and his colleagues want to see if the de novo mutations they have found relate to disease, a step that other studies, even those in top journals, sometimes overlook.

Schizophrenia trailblazers
Compared to other neuropsychiatric research communities, State told SRF, the schizophrenia field is setting the pace of discovery and offers a model for others to follow. He cites the work connecting 22q11 deletions to schizophrenia as a good example of moving from identifying an association to identifying interesting genes and fleshing out the mechanisms by which they could lead to the human phenotype (see SRF related news story; SRF news story; SRF news story; SRF news story).

In his lecture, State said that all treatments for childhood neuropsychiatric disorders have arisen serendipitously, but the new technologies could lead to more rational treatment development. He sees the day dawning when psychiatrists will be able to talk about targeting pathways and mechanisms the same way that their colleagues who treat heart disease, cancer, and diabetes do.—Victoria L. Wilcox.

Bilgüvar K, Öztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, Yalnizoğlu D, Tüysüz B, Çağlayan AO, Gökben S, Kaymakçalan H, Barak T, Bakircioğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yilmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçinkaya C, Kumandaş S, Topçu M, Ozmen M, Sestan N, Lifton RP, State MW, Günel M. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010 Sep 9;467(7312):207-10. Abstract

Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O'Roak BJ, Mason CE, Abbott T, Gupta A, King RA, Pauls DL, Tischfield JA, Heiman GA, Singer HS, Gilbert DL, Hoekstra PJ, Morgan TM, Loring E, Yasuno K, Fernandez T, Sanders S, Louvi A, Cho JH, Mane S, Colangelo CM, Biederer T, Lifton RP, Gunel M, State MW. L-histidine decarboxylase and Tourette's syndrome. N Engl J Med. 2010 May 20;362(20):1901-8. Abstract

Comments on Related News

Related News: 22q11 and Schizophrenia: New Role for microRNAs and More

Comment by:  Linda Brzustowicz
Submitted 21 May 2008
Posted 21 May 2008

While some have expressed frustration over the lack of clear reproducibility of linkage and association findings in schizophrenia, the importance of the chromosome 22q11 deletion syndrome (22q11DS) as a real and significant genetic risk factor for schizophrenia has often been overlooked. While the deletion syndrome is present in a minority of individuals with schizophrenia (estimates of approximately 1 percent), presence of the deletion increases risk of developing schizophrenia some 30-fold, making this one of the clearest known genetic risk factors for a psychiatric illness. As multiple genes are deleted in 22q11DS, it can be a challenge to determine which gene or genes are involved in specific phenotypic elements of this syndrome.

The May 11, 2008, paper by Stark et al. highlights the utility of engineered animals for dissecting the individual effects of multiple genes within a deletion region and provides an important clue into the mechanism likely responsible for at least some of the behavioral aspects of the phenotype. While some may argue about the full validity of animal models of complex human behavior disorders, these systems do have an advantage in manipulability that cannot be achieved in work with human subjects. A key feature of this paper is the comparison of the phenotype of mice engineered to contain a 1.3 Mb deletion of 27 genes with mice engineered to contain a disruption of only one gene in the region, DGCR8. The ability to place both of these alterations on the same genetic background and then do head-to-head comparisons on a number of behavioral, neuropathological, and gene expression assays allows a clear assessment of which components of the mouse phenotype may be attributed specifically to DGCR8 haploinsufficiency. Perhaps not surprisingly, DGCR8 seems to play a role in some, but not all, of the behavioral and neuropathological changes seen in the animals with the 1.3 Mb deletion. The fact that the DGCR8 disruption was able to recapitulate certain elements of the full deletion in the mice does raise its profile as an important candidate gene for some of the neurocognitive elements of 22q11DS, and makes it a potential candidate gene for contributing to schizophrenia risk in individuals without 22q11DS.

Also of great interest is the known function of DGCR8. While the gene name simply stands for DiGeorge syndrome Critical Region gene 8, it is now known that this gene plays an important role in the biogenesis of microRNAs, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. As miRNAs have been predicted to regulate over 90 percent of genes in the human genome (Miranda et al., 2006), a disruption in a key miRNA processing step could have profound regulatory impacts. Indeed, as reported in the Stark et al. paper and elsewhere (Wang et al., 2007), homozygous deletion of DGCR8 function is lethal in mice. What perhaps seems to be the most surprising result is that haploinsufficiency of DGCR8 function does not induce a more profound phenotype, given the large number of genes that would be expected to be affected if miRNA processing were globally impaired. The Stark et al. paper determined that while the pre-processed form of miRNAs may be elevated in haploinsufficient mice, perhaps only 10-20 percent of all mature miRNAs show altered levels, suggesting that some type of compensatory mechanism may be involved in regulating the final levels of the other miRNAs. Still, the 20-70 percent decrease in the abundance of these altered miRNAs could have a profound effect on multiple cellular processes, given the regulatory nature of miRNAs. In the context of the recent evidence for altered levels of some miRNA in postmortem samples from individuals with schizophrenia (Perkins et al., 2007), the Stark et al. paper adds further support for studying miRNAs as potential candidate genes in all individuals with schizophrenia, not just those with 22q11DS. This paper should serve as an important reminder of how careful analysis of a biological subtype of a disorder can reveal important insights that will be relevant to a much broader set of affected individuals.


1. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 May 11; Abstract

2. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006 Sep 22;126(6):1203-17. Abstract

3. Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007 Mar 1;39(3):380-5. Abstract

4. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007 Jan 1;8(2):R27. Abstract

View all comments by Linda Brzustowicz

Related News: Are Membrane Molecules Unmoored in 22q11DS Mouse?

Comment by:  Doron Gothelf
Submitted 27 October 2008
Posted 27 October 2008

The common theory held until recently regarding the genetic underpinning of neuropsychiatric disorders was based on the “common disease-common variant” model. According to that theory, multiple common alleles in the population contribute small-to-moderate additive or multiplicative effects to the predisposition to neuropsychiatric disorders. With the advances in genetic screening technologies this theory is now being challenged. Recent findings indicate that rare copy number variations (CNVs) may account for a substantial fraction of the overall genetic risk for neuropsychiatric disorders including schizophrenia and autism (Consortium, 2008; Stefansson et al., 2008; Mefford et al., 2008). The 22q11.2 microdeletion was the most common CNV identified in patients with schizophrenia in a recent large scale study of patients with schizophrenia (Consortium, 2008). The 22q11.2 microdeletion is also the most common microdeletion occurring in humans and up to one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia by adulthood. Thus the syndrome serves as an important model from which to learn the path leading from a well defined genetic defect to brain development and eventually to the evolution of schizophrenia.

It is still uncertain whether the neuropsychiatric phenotype associated with 22q11.2DS is a result of a strong effect of haploinsufficiency of one or a few genes from the microdeletion region as some studies suggested (Gothelf et al., 2005; Paterlini et al., 2005; Raux et al., 2007; Vorstman et al., 2008), or the result of cumulative small effects of haploinsufficiency of multiple genes, each contributing a small effect, as other studies suggested (Maynard et al., 2003; Meechan et al., 2006).

The current very elegant study by Mukai and colleagues suggests that haploinsufficiency of a single gene from the 22q11.2 deleted region, Zdhhc8, is responsible for the microscopic neural hippocampal abnormalities present in a mouse model of the disease. Remarkably, these abnormalities were prevented with the reintroduction of enzymatically active ZDHHC8 protein. The works of Gogos and his colleagues (Paterlini et al., 2005; Stark et al., 2008) are consistently and brilliantly getting us closer to revealing the complex association between genes from the 22q11.2 region and the neuropsychiatric phenotype. If indeed haploinsuffiency of single genes like Zdhhc8, COMT, or Dgcr8 have a strong effect on abnormal brain development and the eruption of schizophrenia, it conveys an enormous potential for developing novel pathophysiologically based treatments for this refractory disease. Such treatments will target the enzymatic deficit conveyed by the genetic mutation.


[No authors listed]. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Sep 11;455(7210):237-41. Abstract

Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Sep 11;455(7210):232-6. Abstract

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008 Oct 16;359(16):1685-99. Abstract

Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov 1;8(11):1500-2. Abstract

Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, Westphal KG, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005 Nov 1;8(11):1586-94. Abstract

Raux G, Bumsel E, Hecketsweiler B, van Amelsvoort T, Zinkstok J, Manouvrier-Hanu S, Fantini C, Brévière GM, Di Rosa G, Pustorino G, Vogels A, Swillen A, Legallic S, Bou J, Opolczynski G, Drouin-Garraud V, Lemarchand M, Philip N, Gérard-Desplanches A, Carlier M, Philippe A, Nolen MC, Heron D, Sarda P, Lacombe D, Coizet C, Alembik Y, Layet V, Afenjar A, Hannequin D, Demily C, Petit M, Thibaut F, Frebourg T, Campion D. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum Mol Genet. 2007 Jan 1;16(1):83-91. Abstract

Vorstman JA, Chow EW, Ophoff RA, van Engeland H, Beemer FA, Kahn RS, Sinke RJ, Bassett AS. Association of the PIK4CA schizophrenia-susceptibility gene in adults with the 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 21; Abstract

Maynard TM, Haskell GT, Peters AZ, Sikich L, Lieberman JA, LaMantia AS. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8. Abstract

Meechan DW, Maynard TM, Wu Y, Gopalakrishna D, Lieberman JA, LaMantia AS. Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome. Mol Cell Neurosci. 2006 Dec 1;33(4):412-28. Abstract

Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 Jun 1;40(6):751-60. Abstract

View all comments by Doron Gothelf

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Katie Rodriguez
Submitted 7 November 2009
Posted 7 November 2009

If schizophrenia and autism are on a spectrum, how can there be people who are both autistic and schizophrenic? I know of a few people who suffer from both diseases.

View all comments by Katie Rodriguez

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Bernard Crespi
Submitted 12 November 2009
Posted 12 November 2009

One Hundred Years of Insanity: The Relationship Between Schizophrenia and Autism
The great Colombian author Gabriel García Márquez reified the cyclical nature of history in his Nobel Prize-winning 1967 book, One Hundred Years of Solitude. Eugen Bleuler’s less-famous book Dementia Præcox or the Group of Schizophrenias, originally published in 1911, saw first use of the term “autism,” a form of solitude manifest as withdrawal from reality in schizophrenia. This neologism, about to celebrate its centenary, epitomizes an astonishing cycle of reification and change in nosology, a cycle only now coming into clear view as molecular-genetic data confront the traditional, age-old categories of psychiatric classification.

The term autism was, of course, redefined by Leo Kanner (1943) for a childhood psychiatric condition first considered as a subset of schizophrenia, then regarded as quite distinct (Rutter, 1972) or even opposite to it (Rimland, 1964; Crespi and Badcock, 2008), and most recently seen by some researchers as returning to its original Bluelerian incarnation (e.g., Carroll and Owen, 2009). An outstanding new paper by McCarthy et al. (2009), demonstrating that duplications of the CNV locus 16p11.2 are strongly associated with increased risk of schizophrenia, has brought this question to the forefront of psychiatric inquiry, because deletions of this same CNV are one of the most striking recently-characterized risk factors for autism. Additional CNVs, such as those at 1q21.1 and 22q11.21 have also been associated with autism and schizophrenia in one or more studies (e.g., Mefford et al., 2008; Crespi et al., 2009; Glessner et al., 2009), which has led some authors to infer that since an overlapping set of loci mediates risk of both conditions, autism and schizophrenia must be more similar than previously conceived (e.g., Carroll and Owen, 2009; Guilmatre et al., 2009). Similar considerations apply to several genes, such as CNTNAP2 and NRXN1, various disruptions of which have likewise been linked with both conditions (Iossifov et al., 2008; Kirov et al., 2008; Burbach and van der Zwaag, 2009).

So does this plethora of new molecular-genetic data imply that Blueler was indeed correct, if not prescient, that autism and schizophrenia are manifestations of similar disease processes? The answer may appear tantalizingly close, but will likely remain inaccessible without explicit consideration of alternative hypotheses and targeted tests of their differentiating predictions. This approach is simply Platt’s (1964) classic method of strong inference, which has propelled molecular biology so far and fast but left psychiatry largely by the wayside (Cannon, 2009). The alternative hypotheses in this case are clear: with regard to causation from specific genetic and genomic risk factors, autism and schizophrenia are either: 1) independent and discrete, 2) partially yet broadly overlapping, 3) subsumed with autism as a subset of schizophrenia, or 4) diametrically opposite, with normality in the centre. CNVs are especially useful for testing among such alternative hypotheses, because they naturally involve highly-penetrant perturbations in two opposite directions, due to deletions vs duplications of more or less the same genomic regions. Hypotheses 2), 3) and 4) thus predict that autism and schizophrenia should share CNV risk loci, but 2) and 3) predict specific rearrangements (deletions, duplications, or both) shared across both conditions; by contrast, hypothesis (4) predicts that, as highlighted by McCarthy et al. (2009), reciprocal CNVs at the same locus should mediate risk of autism versus schizophrenia. This general approach was pioneered by Craddock et al. (2005, 2009), in their discussion of explicit alternative hypotheses for the relationship between schizophrenia and bipolar disorder, which are now known to share a notable suite of risk alleles.

A key assumption that underlies tests of hypotheses for the relationship between autism and schizophrenia is accuracy of diagnoses. For schizophrenia, this is seldom at issue. However, diagnoses of autism, or autism spectrum disorders such as PDD-NOS, are normally made at an age well before the first manifestations of schizophrenia in adolescence or early adulthood, which generates a risk for false-positive diagnoses of premorbidity to schizophrenia as autism or autism spectrum (e.g., Eliez, 2007). The tendencies for males to exhibit worse premorbidity to schizophrenia than females (Sobin et al., 2001; Tandon et al., 2009), for CNVs to exert severe effects on diverse aspects of early neurodevelopment (Shinawi et al., 2009), and for schizophrenia of earlier onset to exhibit a higher male sex-ratio bias and a stronger tendency to be associated with CNVs rather than other causes (Remschmidt et al., 1994; Rapoport et al., 2009), all suggest a high risk for false-positive diagnoses of autistic spectrum conditions in individuals with these genomic risk factors (Feinstein and Singh, 2007; Reaven et al., 2008; Sugihara et al., 2008; Starling and Dossetor, 2009). Possible evidence of such risk comes from diagnoses of autism spectrum conditions in children with deletions at 15q11.2, 15q13.3, and 22q11.21, and duplications of 16p11.2, CNVs for which schizophrenia risk has been well established from studies of adults (Antshel et al., 2007; Stefansson et al., 2008; Weiss et al., 2008; Ben-Shachar et al., 2009; Doornbos et al., 2009; McCarthy et al., 2009). By contrast, autism-associated CNVs, such as deletions at 16p11.2 (Kumar et al., 2008), or duplications at 22q11.21 (Glessner et al., 2009; Crespi et al., 2009) have seldom also been reported in individuals diagnosed with schizophrenia, which suggests that false-positive diagnoses of schizophrenia as autism are uncommon.

Differentiating between a hypothesis of false-positive diagnoses of premorbidity to schizophrenia as autism, compared to a hypothesis of specific deletions or duplications shared between autism and schizophrenia, requires some combination of longitudinal studies, judicious use of endophenotypes, and adoption of relatively new diagnostic categories such as multiple complex developmental disorder (Sprong et al., 2008). Moreover, to the degree that such false positives are not uncommon, and autism and schizophrenia are underlain by diametric genetically based risk factors, inclusion of children premorbid for schizophrenia in studies on the genetic bases of autism will substantially dilute the probability of detecting significant results.

Ultimately, robust evaluation of alternative hypotheses for the relationship of autism with schizophrenia will require evidence from studies of common and rare SNP variants as well as CNVs, in-depth analyses of the neurodevelopmental and neuronal-function effects of different alterations to genes such as NRXN1, CNTNAP2, and SHANK3, and integrative data from diverse disciplines other than genetics, especially the neurosciences and psychology. Unless such interdisciplinary studies are deployed—in hypothesis-testing frameworks that use strong inference—we should expect to remain, as penned by García Márquez, in “permanent alternation between excitement and disappointment, doubt and revelation, to such an extreme that no one knows for certain where the limits of reality lay”—for yet another 100 years.

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Bleuler E. 1950. Dementia praecox or the group of schizophrenias. (Internat Univ Press, New York). (Translation from 1911 German original).

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Cannon TD. What is the role of theories in the study of schizophrenia? Schizophr Bull. 2009 May;35(3):563-7. Abstract

Carroll LS, Owen MJ. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med. 2009 Oct 30;1(10):102. Abstract

Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005 May;186:364-6. Abstract

Craddock N, O'Donovan MC, Owen MJ. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses. Schizophr Bull. 2009 May;35(3):482-90. Abstract

Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci. 2008 Jun;31(3):241-61; discussion 261-320.

Crespi B, Stead P, Elliot M. Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci U S A. 2009 (in press).

Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC, Hilhorst-Hofstee Y, Hordijk R, Verbruggen KT, Kerstjens-Frederikse WS, van Essen T, Kok K, van Silfhout AT, Breuning M, van Ravenswaaij-Arts CM. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009 Mar-Jun;52(2-3):108-15. Abstract

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View all comments by Bernard Crespi

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Suzanna Russell-SmithDonna BaylissMurray Maybery
Submitted 9 February 2010
Posted 10 February 2010

The Diametric Opposition of Autism and Psychosis: Support From a Study of Cognition
As has been noted previously, Crespi and Badcock’s (2008) theory that autism and schizophrenia are diametrically opposed disorders is certainly a novel and somewhat controversial one. In his recent blog on Psychology Today, Badcock states that the theory stands on two completely different foundations: one in evolution and genetics, and one in psychiatry and cognitive science (Badcock, 2010). While most of the comments posted before ours have addressed the relationship between autism and schizophrenia from a genetic perspective, coming from a psychology background, we note that it is the aspects of Crespi and Badcock’s theory that relate to cognition which have particularly caught our attention. While we can therefore contribute little to the discussion of a relationship between autism and schizophrenia from a genetic standpoint, we present the findings from our recent study (Russell-Smith et al., 2010), which provided the first test of Crespi and Badcock’s claim that autism and psychosis are at opposite ends of the cognitive spectrum.

In placing autism and psychosis at opposite ends of the cognitive spectrum, Crespi and Badcock (2008) propose that autistic and positive schizophrenia traits contrastingly affect preference for local versus global processing, with individuals with autism displaying a preference for local processing and individuals with positive schizophrenia displaying a preference for global processing. That is, these authors claim that while individuals with autism show a tendency to focus on detail or process features in their isolation, individuals with positive schizophrenia show a tendency to look at the bigger picture or process features as an integrated whole. Importantly, since Crespi and Badcock argue for a continuum stretching all the way from autism to psychosis, the same diametric pattern of cognition should be seen in individuals who display only mild variants of autistic and positive schizophrenia traits. This includes typical individuals who score highly on measures such as the Autism Spectrum Quotient (AQ; Baron-Cohen et al., 2001) and the Unusual Experiences subscale of the Oxford-Liverpool Inventory of Experiences (O-LIFE:UE; Mason et al., 2005). These are both reliable and commonly used measures which have been specifically designed to assess the levels of “autistic-like” traits and positive schizotypy traits in typical individuals. Since Crespi and Badcock actually argue their theory is best evaluated with reference to individuals with milder traits of autism and positive schizophrenia, it is with these populations that we investigated their claims.

A task often used to determine whether an individual has a preference for local over global processing is the Embedded Figures Test (EFT; Witkin et al., 1971), which requires individuals to detect hidden shapes within complex figures. As the test requires one to resist experiencing an integrated visual stimulus or gestalt in favor of seeing single elements, it is argued that a local processing style aids successful (i.e., faster) completion of this task (Bolte et al., 2007). Accordingly, from Crespi and Badcock’s (2008) theory, one would expect that relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should perform better on the EFT, while individuals with positive schizotypy traits should perform worse. To test this claim, our study obtained the AQ and O-LIFE:UE scores for 318 students completing psychology as part of a broader degree (e.g., a BSc or BA). Two pairs of groups (i.e., four groups in total), each consisting of 20 students, were then formed. One of these pairs consisted of High and Low AQ groups, which were selected such that they were separated substantially in their AQ scores but matched as closely as possible on their O-LIFE:UE scores. The other pair of groups, the High and Low O-LIFE:UE groups, were selected such that they were separated in their O-LIFE:UE scores, but matched as closely as possible on their AQ scores. The gender ratio was matched closely across the four groups.

To test the prediction that higher levels of autistic-like traits are associated with more skilled EFT performance, the High and Low AQ groups were compared in terms of their mean response time to accurately locate each of the embedded figures. Individuals in the High AQ group did display more skilled EFT performance than individuals in the Low AQ group, consistent with a greater preference for local over global processing in relation to higher levels of autistic-like traits (see also Almeida et al., 2010; Bolte and Poustka, 2007; Grinter et al., 2009; Grinter et al., 2009). We then compared EFT performance for the O-LIFE:UE groups to test the prediction that higher levels of positive schizotypy traits are associated with less skilled performance on this task. Consistent with a preference for global over local processing in relation to higher levels of positive schizotypy traits, individuals in the High O-LIFE:UE group displayed less skilled EFT performance than individuals in the Low O-LIFE:UE group. Therefore, results from both pairs of groups together provide support for Crespi and Badcock’s (2008) claim that autistic and positive schizophrenia traits are diametrically opposed with regard to their effect on local versus global processing.

However, the support our study offers for Crespi and Badcock’s (2008) theory was tempered slightly by our failure to find the expected contrasting patterns of non-verbal relative to verbal ability for our two pairs of groups. To display the expected patterns, relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should have displayed higher non-verbal ability relative to verbal ability, whereas individuals with high levels of positive schizotypy traits should have displayed lower non-verbal relative to verbal ability. While visual inspection of mean verbal and non-verbal scores for the O-LIFE:UE groups revealed a trend consistent with what would be expected based on Crespi and Badcock’s theory, none of the group differences was statistically significant. However, as we pointed out in our article, a study which offers a more complete assessment of this aspect of the theory is warranted. In particular, since the use of a student sample in our study no doubt led to a restriction in the range of IQ scores (especially with reference to verbal IQ), a test of community-based samples would be useful.

Therefore, while Crespi and Badcock’s (2008) theory has passed its first major test at the level of cognition, with our results indicating a contrasting effect of autistic-like and positive schizotypy traits with regard to preference for local versus global processing, further investigation of these authors’ theory at both the cognitive and genetic levels is required.


Almeida, R., Dickinson, J., Maybery, M., Badcock, J., Badcock, D. A new step toward understanding Embedded Figures Test performance in the autism spectrum: The radial frequency search task. Neuropsychologia. 2010 Jan;48(2):374-81. Abstract

Badcock, C. (2010). Diametric cognition passes its first lab test. Psychology Today. Retrieved February 8, from

Baron-Cohen, S., Wheelwright, S., Skinner, R., Martin, J., Clubley, E. (2001). The Autism-Spectrum Quotient (AQ): Evidence from Asperger Syndrome/High-Functioning Autism, males and females, scientists and mathematicians. Journal of Autism and Developmental Disorders, 31, 5-17. Abstract

Bolte, S., Holtmann, M., Poustka, F., Scheurich, A., Schmidt, L. (2007). Gestalt perception and local-global processing in High-Functioning Autism. Journal of Autism and Developmental Disorders, 37, 1493-1504. Abstract

Bolte, S., Poustka, F. (2006). The broader cognitive phenotype of autism in parents: How specific is the tendency for local processing and executive function. Journal of Child Psychology and Psychiatry, 47, 639-645. Abstract

Crespi, B., Badcock, C. (2008). Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences, 31, 241-261. Abstract

Grinter, E., Maybery, M., Van Beek, P., Pellicano, E., Badcock, J., Badcock, D. (2009). Global visual processing and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 1278-1290. Abstract

Grinter, E., Van Beek, P., Maybery, M., Badcock, D. (2009). Brief Report: Visuospatial analysis and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 670–677. Abstract

Mason, O., Linney, Y., Claridge, G. (2005). Short scales for measuring schizotypy. Schizophrenia Research, 78, 293-296. Abstract

Russell-Smith, S., Maybery, M., Bayliss, D. Are the autism and positive schizotypy spectra diametrically opposed in local versus global processing? Journal of Autism and Developmental Disorders. 2010 Jan 28. Abstract

Witkin, H., Oltman, P., Raskin, E., Karp, S. (1971). A manual for the Embedded Figures Test. Palo Alto, CA: Consulting Psychologists Press.

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Related News: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model

Comment by:  Anthony-Samuel LaMantia
Submitted 5 April 2010
Posted 5 April 2010

In a recent report, Sigurdsson et al. provide data that synchrony between hippocampal and cortical activity is subtly altered during a specific spatial motor memory task in a mouse model of the 22q11 Deletion syndrome (also known as DiGeorge syndrome). There have been several studies of other mouse models of 22q11 Deletion syndrome, the first of which were published in the late 1990s and early 2000s (Lindsey et al., 1999; Merscher et al., 2001). All of the data indicate that the development and function of the cerebral cortex is compromised by diminished dosage of the approximately 30 genes whose deletion is obligate in the disease. The reason for the intense interest in 22q11 Deletion syndrome is the high (but not invariant) incidence of schizophrenia in patients with this genetic disorder.

The likely disruption of hippocampal/cortical circuitry, based on subtly altered synchrony (but not, apparently, synaptic connectivity) makes sense if one assumes that diminished dosage of 22q11 genes compromises local circuit organization without wholesale changes in basic mechanisms of synaptic communication. Such results can be compared—cautiously—to hypotheses of regional/circuit malfunction in schizophrenic patients. The synchrony argument is intriguing, especially given the currency of models of cognition that invoke oscillatory behavior of forebrain circuits to explain coherence between diverse, related representations that are thought necessary for cognition and complex behaviors. Nevertheless, it is not clear that current experimental methods in humans can identify the subtle task-dependent dysregulation of synchrony that goes awry in the mouse. Thus, the report by Sigurdsson et al., while intriguing, provides a novel starting point for further investigation. Several questions arise in the mouse model: is cortical or hippocampal circuitry compromised in some way that goes beyond detectable changes in synaptic transmission? If so, how? Is some additional neuronal population that receives information from or provides input to both regions compromised by 22q11 deletion? Finally, how do such abnormalities arise? Are they the result of altered development, or disruptions in mature neuronal function?

While these observations raise exciting possibilities for further research in the relationship between 22q11 Deletion syndrome and schizophrenia pathology, some issues should be considered when comparing the mouse work and human disease. It remains difficult to confirm whether the sort of spatial memory tasks used by Sigurdsson et al. are really examples of mouse “executive function,” “working memory,” or the sorts of cognitive domains thought to be selectively compromised in schizophrenic patients. Moreover, it is generally agreed by comparative neuro-anatomists that the mouse does not have "prefrontal cortex" that is comparable to that seen in non-human and human primates—especially the dorsolateral prefrontal cortex. In humans, the performance of working memory tasks relies upon the integrity of this region, and its connections with a number of other cortical and subcortical areas. These circuits remain the focus of investigation in human schizophrenia pathology. Thus, while dysregulation of hippocampal activity and motor association cortical activity in the frontal aspect of the mouse brain (which is not actually prefrontal cortex) is likely occurring in 22q11 Deletion syndrome model mice, additional work must be done to determine how this relates to human behavioral disruptions in schizophrenia.


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Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell . 2001 Feb 23 ; 104(4):619-29. Abstract

View all comments by Anthony-Samuel LaMantia

Related News: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model

Comment by:  Wendy Kates
Submitted 7 April 2010
Posted 8 April 2010

The links between genetic variants, neural circuitry, and cognitive dysfunction in schizophrenia are not well understood, due in part to the diagnostic and etiological heterogeneity of schizophrenia, which creates enormous challenges to understanding its pathophysiology. Several research groups are responding to this challenge by investigating the etiologically homogeneous microdeletion disorder, 22q11.2 deletion syndrome (22q11.2 DS), which poses the highest known genetic risk for schizophrenia, second only to having two parents with the disorder. Accordingly, 22q11.2 DS is a compelling model for understanding the pathophysiology of cognitive dysfunction in schizophrenia. Gogos, Karayiorgou, Sigurdsson, and colleagues are investigating this issue with a mouse model of 22q11.2 DS, and their latest, high-impact study of functional connectivity in the context of a working memory paradigm has brought us palpably closer to understanding these elusive links. They elegantly demonstrate that the 22q11.2 microdeletion disrupts prefrontal-hippocampal synchrony, which, in turn, likely contributes to impairments in working memory performance.

Although the specific genes within the microdeletion that are linked to neurocognitive deficits still need to be identified, this study begins to disentangle the complex associations among genetic variants, neural connectivity, and cognition in 22q11.2 DS. The elegance of a mouse model is that it can utilize methods that provide exquisite temporal and spatial resolution that is very difficult to obtain in human studies. Thus, this study identifies, at the neuronal level, disruptions in timing and connectivity that may underlie the white matter deficits that have been observed in neuroimaging studies (Barnea-Goraly et al., 2003; Kates et al., 2001; Simon et al., 2005) of patients with this genetic syndrome, and that putatively account for some of the syndrome’s prominent neurocognitive deficits. These findings provide support for future, more focused studies of neural connectivity, using EEG and diffusion tensor imaging, in patients with this mutation as well as the larger population of patients with schizophrenia.


Barnea-Goraly N, Menon V, Krasnow B, Ko A, Reiss A, Eliez S. (2003) Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study. Am J Psychiatry, 160 (10): 1863-9. Abstract

Kates WR, Burnette CP, Jabs EW, Rutberg J, Murphy AM, Grados M, Geraghty M, Kaufmann WE, Pearlson GD. (2001) Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol Psychiatry, 49 (8): 677-84. Abstract

Simon TJ, Ding L, Bish JP, McDonald-McGinn DM, Zackai EH, Gee J. (2005) Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study.Neuroimage. 25 (1): 169-80. Abstract

View all comments by Wendy Kates