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Schizophrenia: a common disease caused by multiple rare alleles

  • Jon M. McClellan (a1), Ezra Susser (a2) and Mary-Claire King (a3)

Summary

Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This ‘common disease – rare alleles' hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits. We review the implications of this model for gene discovery research in schizophrenia.

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Copyright

Corresponding author

Dr Jon McClellan, Department of Psychiatry, Box 356560, University of Washington, Seattle, WA 98195, USA. Email: drjack@u.washington.edu

Footnotes

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See invited commentary pp. 200–203, this issue

Declaration of interest

None. Funding detailed in Acknowledgements.

Footnotes

References

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Schizophrenia: a common disease caused by multiple rare alleles

  • Jon M. McClellan (a1), Ezra Susser (a2) and Mary-Claire King (a3)

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Schizophrenia: a common disease caused by multiple rare alleles

  • Jon M. McClellan (a1), Ezra Susser (a2) and Mary-Claire King (a3)
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eLetters

Anticipation and the genetics of psychosis

Mark Agius, Senior Rasearch Fellow
02 May 2007

A theoretical model should explain all of the observed facts.Both the model of schizophrenia which proposes many genes of small effect [McClellan 2007] and that which proposes few gene mutations of large effect [Craddock 2007] explain many of the observed facts. In particular, the model of many genes of small effect explain the observed spectrum of mental illness from bipolar disorder, through schizoaffective disorder to schizophrenia.However, we have both observed schizophrenia occurring in particular families. One of us has observed a number of south asian families with multiple cases of schizophrenia. In some of these families, it has been noted that patients of a second generation develop the illness at a much younger age compared to their parents. The illness was more severe in the second generation. [Agius 2003] Thus far we have assumed that these observations were related to the concentration of many genes of small effect within these families.One of us has also observed the same effect, known as anticipation in a group of families in Slovenia. Anticipation describes decreasing age of onset and increased disease severity in the second generation. Thirty-six parent-offspring pairs of schizophrenic patients, were studied.First hospital admission was used as a proxy for disease onset. In the offspring group [OG], onset was identified as 23.5 years, and 39.6 years was the age at onset in the parent group[PG]. There was a higher mean total number of days of hospitalisation in the first five years of treatment in the offspring group [OG=223, PG=161] , and there were a higher mean number of hospitalisations in the first five years of treatment in the OG group [OG=7.27, PG=7.51]. These two measures were used as a proxy for increased intensity of illness. The OG group had a higher level of education, but demonstrated fewer working years and had less children. [Blinc 2002]What arises is the question of whether the ‘many genes of small effect’ orthe ‘few genes of large effect’ model is best suited to explaining this observation of anticipation in schizophrenia.

[1] McClellan JM, Susser E, King MC 2007 Schizophrenia; a common disease caused by multiple rare alleles British Journal of Psychiatry 190;194-199.[2] Craddock N, O’Donovan M.C., Owen MJ. 2007 Phenotypic and genetic complexity of psychosis. Invited commentary on…. Schizophrenia; a common disease caused by multiple rare alleles British Journal of Psychiatry 190;200-203.[3] Agius M, Gallagher O, Zaman R 2003 Young Asian Psychotic Patients in Luton; The development of an Early Intervention service for Ethnic Minority Patients.. ‘Psychiatric care across cultures’ First pan-Mediterranean conference on psychiatry and cultures Malta p109 isbn99909-44-23-7[4] Blinc M 2002. Druzinsko pojavljanji schizophrenije-Znacilinosti starsev in njihovih potomcev , obolelih za schizofrenijo. The appearance of schizophrenia in families-The characteristics of parents of the illnessin the parents and their offspring. Masters thesis University of Ljubljana.
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Conflict of interest: None Declared

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Re: Rare alleles, weak polygenes or the speciation event

Jon McClellan, Associate Professor of Psychiatry
11 April 2007

We are delighted that our commentary has stimulated discussion about strategies for gene discovery in schizophrenia. The thoughtful comments of Craddock and colleagues (1) and of Crow (2) provide us the opportunity to clarify some key points.

We agree that schizophrenia, like other complex traits, will be influenced by a large number of genetic and epigenetic events with a spectrum of effects. Both rare alleles of large effect and common allelesof modest effect are likely to be discovered. Rare severe-effect alleles are fully compatible with familial patterns of schizophrenia, because many(perhaps most) such alleles have arisen de novo in the present or recent generations. De novo mutations play havoc with predictions of conventional recurrence risk models. For example, de novo meiotic mutations (in the parental germline) increase disease concordance among MZtwins but not among DZ twins. In contrast, de novo mitotic mutations or epigenetic events (in early embryogenesis) reduce concordance among both MZ and DZ twins.

Genetic association studies are not the most straightforward path to gene discovery for schizophrenia. Individually rare alleles cannot be identified by comparing frequencies of common alleles among unrelated cases versus controls, even with enormous numbers of well-diagnosed cases,properly matched controls, and very dense (and expensive) screening tools.To the extent that rare alleles are important to schizophrenia, study designs based on a naive common disease-common allele model will yield variable and nonreplicable results (3).

Characteristic patterns of age at onset, gender differences, and brain changes associated with schizophrenia are fully compatible with causal influences of rare severe-effect events, either genetic or epigenetic. Each such event alters the expression, timing, or function of one of a very large number of genes. The products of these genes convergein common pathways. Aberrations of a pathway by any of multiple mechanismsmay lead to clinically similar disorders.

Crow’s proposition that schizophrenia arises from the disruption of uniquely human genetic elements is very appealing. This premise, however, need not narrow the search for causes, genetic, epigenetic or environmental. Human speciation likely occurred primarily due to regulatory changes in genes, rather than to common polymorphisms leading to changes in gene sequence (4). The extraordinary number of repeated elements in the human genome gave rise to a vast number of new genes and regulatory mechanisms. Their architecture also created an increased risk for copying errors. Thus, one cost of the genomic complexity that enabledhuman brain development may be a de novo error rate that results in the maintenance of schizophrenia in the population.

Autism has recently been shown to be associated with a significantly increased frequency of rare de novo mutations (5). These results presage the identification of many more rare mutations associated with other neurodevelopmental illnesses, as advancing technology enables the detection of ever-smaller genomic lesions. The ultimate resolution of thisdebate lies in gene discovery, for which we therefore encourage the application of study designs most likely to be fruitful.

Declaration of Interest: The authors have no conflicts of interest to report.

Craddock N., O'Donovan M. C., Owen M. J. (2007) Phenotypic and genetic complexity of psychosis: Invited commentary on ... Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry, 190, 200-3.

Crow T. J. (2007) Rare alleles, weak polygenes or the speciation event. Br J Psychiatry eletter March 9

King M. C., Ahsan H., Susser E. (2006) Designs for the Genomic Era. In Susser E, Schwartz S, Morabia A, and Bromet EJ, Psychiatric Epidemiology: Searching for the Causes of Mental Disorders, pp 401-412. New York: Oxford University Press

King M. C, Wilson A. C. (1975) Evolution at two levels in humans and chimpanzees. Science, 188, 107-16

Sebat J., Lakshmi B., Malhotra D., et al., (2007) Strong Association of De Novo Copy Number Mutations with Autism. Science, Mar 15, epub
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Rare alleles, weak polygenes or the speciation event?

Timothy J Crow
11 April 2007

In their “common disease – rare alleles” hypothesis McClellan el al come close to formulating an untestable theory. Although they refer to currently fashionable “candidate genes” eg dysbindin, neuregulin and DISC-1 it appears that they do not regard these as established. I agree that there is no consistency in the findings across even the largest genome scans conducted to date (sample sizes exceeding 300 and totalling over 1,000 [1] sibpairs) but disagree profoundly about the alternative.

What we know about schizophrenia is –

1. Incidences are more uniform across populations as one moves to thecore syndrome, eg nuclear symptoms [2].

2. Structural brain changes, eg ventricular enlargement, are consistent across populations [3] and uniform across patients relative to controls [4].

3. Age of onset has a specific distribution throughout the reproductive phase of life.

4. There are sex differences (earlier onsets and worse outcomes in males).

5. The core syndrome comprises symptoms that are language related, ie Homo sapiens-specific.

None of these findings would be expected if schizophrenia were due torandom mutations in a large number of genes such as McClellan et al postulate. Nor would one expect there to be variation in form of illness within families as is generally observed.

While McClelland et al’s hypothesis promises a search for elusive rare alleles that will never reach a conclusion Craddock et al in their commentary perseverate in their claim that “Several genes have been implicated repeatedly as conferring risk for schizophrenia and bipolar disorder”. Comparison of the largest and most systematic linkage studies (1) including those of the Cardiff group themselves shows that these claims cannot be sustained

Alternative hypotheses to the “rare allelles of major effect” and the“polygenes of small effect” deserve consideration. One such (1) is that the variation arises in relation to characteristics that are specifically human, ie recent in evolution, and that it is “epigenetic” in form, ie involves a modification of the sequence (methylation of DNA) or the associated chromosomal structure (methylation, phosphorylation or acetylation of histones) rather than a change in the DNA sequence itself. What we know is that the risk to first-degree relatives is approximately 10%, whereas the risk to second-degree relatives is very little increased compared to the population as a whole. While this is often held to be consistent with polygenic influence it is also compatible with an “imprint” that is applied and re-applied in meiosis, ie with a short time course between generations. The solution proposed is that the variation arises in relation to the change (speciation event) that defined the species, and that this is associated with the cerebral torque – the bias from right frontal to left occipital across the anteroposterior axis that is characteristic of the human brain. By contrast to McClellan et al’s rare alleles and Craddock et al’s polygenes of small effect this hypothesis is specific and refutable – a gene has been identified that duplicated at 6 million years from the X to the Y chromosome,to give rise to the ProtocadherinX/Y gene pair. This pair has been subject to accelerated evolution since the duplication event [5] and is in an unusualsituation with respect to epigenetic modulation.This variation can be assessed and the hypothesis thereby tested.

Yours sincerely

TJ CrowReference List

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

2. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JEet al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization Ten Country Study. Psychol Med 1992; Suppl 20: 1-97.

3. Chua SE, Lam IWS, Tai KS, Cheung C, Tang WN, Chen EYH et al. Brain morphological abnormality in schizophrenia is independent of countryof origin. Acta Psychiatr Scand 2003; 108: 269-275.

4. Vita A, Dieci M, Silenzi C, Tenconi F, Giobbio GM, Invernizzi G. Cerebral ventricular enlargement as a generalized feature of schizophrenia: a distribution analysis on 502 subjects. Schiz Res 2000; 44: 25-34.

5. Williams NA, Close J, Giouzeli M, Crow TJ. Accelerated evolution of Protocadherin11X/Y: A candidate gene-pair for cerebral asymmetry and language. Am J Med Genet (Neuropsychiatric Genet) 2006; 141B: 623-633.
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Conflict of interest: None Declared

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Rare alleles, weak polygenes or the speciation event

Timothy J Crow
09 March 2007

Re: Rare alleles, weak polygenes or the speciation event

In their “common disease – rare alleles” hypothesis McClellan el al come close to formulating an untestable theory. Although they refer to some currently fashionable “candidate genes” eg dysbindin, neuregulin and DISC-1 it appears that they do not regard these as established. I agree that there is no consistency in the findings across even the largest genome scans conducted to date (sample sizes exceeding 300 and totalling over 1,000 [1] sibpairs) but disagree profoundly about the alternative.

What we know about schizophrenia is –

1. Incidences are more uniform across populations as one moves to thecore syndrome, eg nuclear symptoms [2].

2. Structural brain changes, eg ventricular enlargement, are consistent across populations [3] and uniform across patients relative to controls [4].

3. Age of onset has a specific distribution throughout the reproductive phase of life.

4. There are sex differences (earlier onsets and worse outcomes in males).

5. The core syndrome comprises symptoms that are language related, ie Homo sapiens-specific.

None of these findings would be expected if schizophrenia were due torandom mutations in a large number of genes such as McClellan et al postulate. Nor would one expect there to be variation in form of illness within families as is generally observed.

The alternative is that the variation arises in relation to characteristics that are specifically human, ie recent in evolution, and that the variation is “epigenetic” in form, ie involves a modification of the sequence (methylation of DNA) or the associated chromosomal structure (methylation, phosphorylation or acetylation of histones) rather than a change in the DNA sequence itself. What we know is that the risk to first-degree relatives is approximately 10%, whereas the risk to second-degree relatives is very little increased compared to the population as a whole. While this is often held to be consistent with polygenic influence it is also consistent with an “imprint” that is applied and re-applied in meiosis, ie with a short time course between generations. The solution I have proposed is that the variation arises in relation to the change (speciation event) that defined the species, and that this is associated with the cerebral torque – the bias from right frontal to left occipital across the anteroposterior axis that is characteristic of the human brain.By contrast to McClellan et al’s thesis this hypothesis is refutable – a gene (ProtocadherinX/Y) that duplicated at 6 million years from the X to the Y chromosome, and has been subject to accelerated evolution subsequently [5] has been identified and is in an unusual situation with respect to epigenetic modulation. While McClelland et al’s hypothesis promises a search for elusive rare alleles that will never reach a conclusion Craddock et al in their commentary reiterate their claim that “Several genes have been implicated repeatedly as conferring risk for schizophrenia and bipolar disorder”. Comparison of the largest and most systematic linkage studies (1) including those of the Cardiff group themselves shows that these claims cannot be sustained. Alternative hypotheses to the “rare allelles of major effect” and the “polygenes of small effect” therefore deserve a hearing. One such is epigenetic variation at the speciation locus - the gene that was subject to critical change at the origin of the species (1,5).

Yours sincerely

TJ Crow

Reference List

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

2. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JEet al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization Ten Country Study. Psychol Med 1992; Suppl 20: 1-97.

3. Chua SE, Lam IWS, Tai KS, Cheung C, Tang WN, Chen EYH et al. Brain morphological abnormality in schizophrenia is independent of countryof origin. Acta Psychiatr Scand 2003; 108: 269-275.

4. Vita A, Dieci M, Silenzi C, Tenconi F, Giobbio GM, Invernizzi G. Cerebral ventricular enlargement as a generalized feature of schizophrenia: a distribution analysis on 502 subjects. Schiz Res 2000; 44: 25-34.

5. Williams NA, Close J, Giouzeli M, Crow TJ. Accelerated evolution of Protocadherin11X/Y: A candidate gene-pair for cerebral asymmetry and language. Am J Med Genet (Neuropsychiatric Genet) 2006; 141B: 623-633.
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