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SPECIAL ARTICLES |
Department of Psychiatry, University of Washington, Seattle
Department of Epidemiology, Mailman School of Public Health, Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York
Department of Genome Sciences and Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA
Correspondence: Dr Jon McClellan, Department of Psychiatry, Box 356560, University of Washington, Seattle, WA 98195, USA. Email: drjack{at}u.washington.edu
Funding detailed in Acknowledgements.
See invited commentary, pp.
200–203, this
issue 
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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We suggest that the `common disease – rare alleles' model explains many cases of schizophrenia. Our hypothesis is that many mutations predisposing to schizophrenia are highly penetrant and individually rare, even specific to single patients or families. In this model, different families harbour different mutations, either in the same gene or in different genes, but any one family carries only one or two mutations. Many different disease-associated mutations may occur in the same gene.
The `common disease – common alleles' and `common disease – rare alleles' models are not mutually exclusive (Goldstein & Chikhi, 2002). Rare severe mutations may occur in genes that also harbour more common variants with modest effects on disease risk. However, the two models have distinctly different implications for gene-finding strategies. Most current psychiatric genetic research is designed to identify common alleles or haplotypes associated with with increased risk of disease and shared by large numbers of patients compared with appropriate controls (Merikangas & Risch, 2003). If many cases of schizophrenia stem from individually rare large-effect alleles, current approaches – even if executed perfectly – will fail to identify critical genes.
We argue that current observations from epidemiology and genetics of schizophrenia are consistent with the influence of a large number of individually rare deleterious mutations, many of which have occurred in the present or recent generations. Several features of schizophrenia support this view:
To explain our reasoning, we first describe recent findings in genomics and genetics of other complex human disorders. Then we show that the results of schizophrenia research are consistent with the existence of multiple individually rare alleles of large effect. Finally, we consider the implications of this model for future schizophrenia research.
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THE HUMAN GENOME |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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GENETIC HETEROGENEITY IN HUMAN DISEASE |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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To the extent that any class of mutation – point mutations, copy number errors or abnormalities of chromosome number – occur spontaneously, they appear at similar rates in all human populations. All humans share the same basic genomic architecture, including the same genomic regions vulnerable to mutations. The incidence of schizophrenia does not appear to vary substantially across populations by virtue of genetic ancestry. This pattern is consistent with a disease due to multiple, independent de novo mutations that arise in many different vulnerable genes and genomic regions. Furthermore, environmental exposures with mutagenic consequences may lead to high rates of new mutations among exposed individuals. For example, environmental factors such as maternal starvation that are associated with disease (Cannon (et al, 2003) may mediate their effects through de novo genetic or epigenetic mutations. We explore this theme in more detail below.
Complex illnesses are almost universally characterised by allelic heterogeneity (multiple different mutations in the same gene leading to disease) and locus heterogeneity (mutations in multiple different genes leading to the same disease) (Botstein & Risch, 2003; Goldstein et al, 2003). We propose that both are characteristic of schizophrenia. To understand the potential implications of genetic heterogeneity for schizophrenia, we briefly consider other complex disorders for which genes have been identified.
Deafness
To date, nearly a hundred genes have been identified that harbour inherited
mutations leading to hearing loss (Petit
et al, 2001; Friedman
& Griffith, 2003). All mutations are recent and all but one
are individually rare. The one frequent mutation, 30delG in connexin 26, is
the exception that proves the rule, in that the same mutation has occurred
independently numerous times in a mutational hot-spot.
Epilepsy
The inherited forms of epilepsy are characterised by allelic and locus
heterogeneity (Meisler (et al,
2001). Mutations in any of several genes involved with neuronal
signalling can lead to broadly defined epilepsy. Rare mutations in three
different sodium channel genes lead to one more narrowly defined form of
epilepsy (generalised epilepsy with febrile seizures plus).
Alzheimer's disease
Alzheimer's disease illustrates that the `common disease – common
allele' and `common disease – rare allele' models need not be mutually
exclusive. The common 
4 allele of APOE (apolipoprotein E) is
associated with a threefold to fourfold increased risk in individuals of
European descent of developing common, late-onset Alzheimer's disease
(Bird, 2005). On the other
hand, multiple rare mutations in genes encoding amyloid precursor protein
(APP), presenilin 1 and 2 (PS1 and PS2) and
ubiquilin 1 (UBQLN1) are responsible for familial early-onset
Alzheimer's disease. Therefore, both common modest-effect alleles and rare
large-effect alleles have a role in Alzheimer's disease. The role of
APOE4 is an excellent example of the `common disease – common
allele' model. However, the effect of APOE4 on Alzheimer's disease
risk is substantially larger than the effect sizes of 2 or less that are
typically estimated for schizophrenia susceptibility genes.
Inherited predisposition to cancer
In each of the two major genes for inherited breast and ovarian cancer,
BRCA1 and BRCA2, more than a thousand different pathogenic
mutations have been found (Walsh et
al, 2006). Large genomic rearrangements account for about 10%
of these mutations. All inherited BRCA1 and BRCA2 mutations
are individually rare. Both locus and allelic heterogeneity are also
characteristic of inherited colon cancer and the rarer cancer syndromes
(Vogelstein & Kinzler,
2004).
Lipid metabolic pathways
Rare variants in genes related to lipid metabolism are associated with low
levels of high-density lipoprotein cholesterol (HDL–C)
(Cohen et al, 2004)
and low-density lipoprotein cholesterol (LDL–C)
(Cohen et al, 2006).
Although each variant is individually rare, in total these variants are found
in a substantial portion of individuals at the far end of the spectrum in
terms of levels of HDL–C or LDL–C respectively.
These examples illustrate two ways in which mutations of large effect are important for understanding human disease. First, the collective effect of individually rare mutations in the same gene may explain a considerable proportion of an illness. Second, rare mutations in genes of large effect can reveal pathways critical to disease development.
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IMPLICATIONS OF GENETIC HETEROGENEITY FOR GENE DISCOVERY |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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Currently, most gene-discovery strategies for schizophrenia research – case–parent triad studies, candidate gene studies and haplotype association studies – are designed to identify alleles or haplotypes that appear more frequently among affected individuals than among appropriate controls (Cannon et al, 2003). These designs are not robust to either allelic heterogeneity or locus heterogeneity. Sib-pair linkage analyses are designed to detect genomic regions consistently shared by affected siblings. Sib-pair analyses are robust to allelic heterogeneity but not to locus heterogeneity. For each of these designs, hundreds or thousands of rigorously diagnosed cases of unrelated affected and unaffected individuals are examined. If a substantial portion of schizophrenia stems from different individually rare alleles, increasing the number of cases also increases the number of different disease risk mutations represented among them. As a result, increasing sample size does not confer a corresponding increase in statistical power. In the most extreme scenario, in which every case results from a different mutation, an increase in sample size would not lead to any increase in the power to detect any one mutation. Consequently, even very large studies may fail to detect individually rare disease risk mutations.
In addition, genetic analyses that focus only on single nucleotide polymorphisms (SNPs), either individually or in haplotypes, rather than fully sequenced DNA, will inevitably miss rare disease alleles and thus fail to detect critical genes harbouring such alleles. Association and linkage studies generally assume that individuals sharing the same SNP-defined haplotype share the entire region, including any hypothetical embedded disease alleles. This assumption is reasonable for ancient alleles and nearly always true for related individuals for whom there is direct inheritance of the haplotype. However, this assumption is not reasonable for a study of unrelated individuals who carry disease alleles of recent origin. Rare recent mutations causing schizophrenia within the same haplotype will differ among unrelated individuals, diluting any association.
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TWO CANDIDATE GENES FOR SCHIZOPHRENIA: DYSBINDIN AND DISC1 |
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Candidate genes have been suggested in several of these regions, including dysbindin on 6p22, neuregulin on 8p22, G72 on 13q34, COMT on 22q11, RGS4 on 1q21 and GRM3 on 7q21 (see reviews by Blouin et al, 1998; Harrison & Weinberger, 2005). Each of these genes is biologically plausible (Owen et al, 2004). However, for each candidate gene, both positive and negative associations have been reported with the same SNPs; strengths of effects are generally weak; the specific allele or haplotype associated with the illness varies across studies; and definitive causative mutations have not been identified.
To illustrate the implications of the common allele v. rare allele models, we will review two promising susceptibility genes, dysbindin (DTNBP1) and DISC1. Very different study designs revealed these genes, with correspondingly different results to date. Linkage, association and functional studies all support some role for dysbindin in schizophrenia. Several studies involving different populations have found positive associations of dysbindin alleles or haplotypes with schizophrenia (Straub et al, 2002; Schwab et al, 2003; Funke et al, 2004; Kirov et al, 2004; Kohn et al, 2004; Numakawa et al, 2004; Williams et al, 2004; Bray et al, 2005; Gornick et al, 2005). Dysbindin is widely expressed in brain, and appears to play a part in cognitive functioning and capacity (Owen et al, 2004). Post-mortem studies suggest that brain levels of dysbindin may be reduced in individuals with schizophrenia (Weickert et al, 2004). However, no variant of dysbindin has been specifically linked to schizophrenia. Across different studies, the risk conferred by any dysbindin variant is small, with effect sizes of about 2.0 or less. Among positive association studies, the specific alleles associated with the disease differ. Moreover, an allele may be associated with increased disease risk in some studies and decreased risk in others (Owen et al, 2004). In general, the variants of interest (defined by SNPs) are common and without known functional significance. An exception is SNP rs1047631, which has been associated with differences in the expression of dysbindin in brain (Funke et al, 2004). However, the frequency of the haplotype with this SNP was similar between cases (45.6%) and controls (40.4%). Thus far, resequencing efforts have not revealed any coding sequence mutations in dysbindin among individuals with schizophrenia (Liao & Chen, 2004).
Therefore, at present the evidence supporting dysbindin is mixed. Variable associations with different alleles have been attributed to allelic heterogeneity; yet allelic heterogeneity refers to different disease-causing mutations in the same gene, not to the same allele reducing risk in some cases and increasing risk in others. There are at least three possible interpretations of these data. The most favoured in the literature is that dysbindin variants mediate disease risk as part of a complex interaction with other genes and environmental factors. This is possible, in principle, although difficult to test given the challenge of establishing the role of a mediating factor of small effect on a complex illness of unknown cause.
A second possibility is that relatively rare, as yet unidentified variants in the dysbindin locus are embedded in illness-associated haplotypes in some, but not all, cases (including those potentially located in non-coding regulatory regions). Such alleles could have substantial effects on the phenotype, but would be masked by studying only the common haplotype. The third possibility is that many, most, or all of the various positive associations with dysbindin are false positives. The number of different positive association studies (albeit with different variants) is taken as prima facie evidence that the gene must be involved with the disorder. However, dysbindin, like many genes involved with brain development, is large (> 140 kb). The dysbindin locus includes at least 363 SNPs (Hinrichs et al, 2006), from which various candidates are selected for association studies. Incorporating linkage disequilibrium across the locus, many thousands of SNP and haplotype combinations appear in different populations. The potential for false positives is enormous. Unless negative and positive studies were published with equal frequency, this possibility is also nearly impossible to test.
In contrast, DISC1 and its associated non-coding antisense RNA DISC2 were originally identified by a balanced translocation involving chromosome 1q42 which segregated with schizophrenia (and other major psychiatric disorders) over four generations in a large Scottish kindred (St Clair et al, 1990; Millar et al, 1998, 2000). Sachs et al (2005) found that a frameshift mutation that abnormally truncates DISC1 co-segregated with schizophrenia in three siblings. However, this mutation is also rarely found in controls with unknown diagnostic status (Green et al, 2006). The gene PDE4B (phosphodiesterase 4B), which interacts with DISC1 in the neuronal cyclic adenosine monophosphase (AMP) pathway, was disrupted by a balanced translocation in two related individuals with chronic psychotic illnesses (Millar et al, 2005). Finally, mice with a deletion variant that disrupts the DISC1 protein have working memory deficits (Koike et al, 2006). These findings suggest a role of rare large-effect mutations of DISC1 and of genes involved in DISC1 pathways in the development of schizophrenia.
Not surprisingly, DISC1 became the subject of association studies. Haplotypes of DISC1 were associated with schizophrenia and other mental illness in European and North American populations (Ekelund et al, 2001; Hennah et al, 2003; Hodgkinson et al, 2004; Callicott et al, 2005; Cannon et al, 2005; Hamshere et al, 2005) but not in Japanese or Scottish populations (Devon et al, 2001; Kockelkorn et al, 2004; Zhang et al, 2005). Within populations with positive associations, DISC1 haplotypes were also associated with putative endophenotypes, including neuroanatomical and/or neurocognitive profiles (Hodgkinson et al, 2004; Burdick et al, 2005; Cannon et al, 2005). However, disease-risk haplotypes vary across populations and effect sizes are small. Therefore, although there is compelling evidence that rare large-effect mutations in DISC1 are associated with schizophrenia, it is not clear whether common polymorphisms play a part.
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IMPLICATIONS FOR GENETIC RESEARCH IN SCHIZOPHRENIA |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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We propose an alternative strategy in selecting cases for study. Rare cases of schizophrenia with mutations that can be individually detected using current genomic technologies are extremely valuable. It is worthwhile devoting resources to finding them. It has been recognised for decades that such cases would include any large kindred with a number of well-diagnosed individuals or cases with identifiable genomic events of recent origin (e.g. balanced translocations). The emerging story of DISC1 highlights this strategy, since the gene was originally identified by a balanced translocation on chromosome 1q42 coinherited with schizophrenia (Millar (et al, 1998). Similar promising findings have been noted for specific genes in the 22q11 region (Maynard et al, 2002), stemming in part from the recognised association between deletions at 22q11 (i.e. the velo-cardio-facial syndrome) and schizophrenia.
Current genomic technology now enables the identification of an increasingly large number of classes of mutations. Heretofore, identifiable genomic events have been limited to chromosomal abnormalities such as translocations or deletions. However, as the resolution of genome-wide mutation screening technologies improves, smaller genomic events in informative cases or families can be detected. Once identified, a gene altered by a single chromosomal event becomes a candidate to be screened for other (typically smaller) mutations in other cases. Advanced resequencing technology allows for more rapid identification of mutations in candidate genes. The occurrence of multiple deleterious mutations among unrelated cases provides both biological evidence and epidemiological support for the causal role of the gene, using gene-based hypothesis testing strategies (Chen et al, 2006).
Individuals who develop schizophrenia following a known environmental exposure are also potentially informative. Such exposures may focus gene discovery in two ways. First, genomic approaches (e.g. resequencing efforts) can focus on candidate genetic pathways relevant to the suspected exposure, screening for otherwise benign variants that are deleterious given the exposure. For example, associations between schizophrenia and in utero exposure to maternal starvation (Susser (et al, 1996; St Clair et al, 2005), and associations between schizophrenia and genes in the folate metabolic pathway (Lewis et al, 2005; Picker & Coyle, 2005) suggest that mutations in genes in the folate metabolism network could be linked to the illness. Second, the mutagenic effects of the environmental exposure can be evaluated. Following the same example, gestational folate deficiency may be mutagenic, in that it leads to an increase in the rate of mutation genome-wide (McClellan et al, 2006). Among such cases, genome-wide mutational screening may detect de novo mutations. If disease-associated alleles are identified, other mutations within the same gene may confer some risk for other individuals with the same exposure. Furthermore, severe mutations in the same gene may lead to the disorder without the exposure.
As informative cases are identified, genomic technologies are needed for efficient screening for potential disease-associated mutations. Effective transcriptome and proteome-based tools are needed to characterise such variants. These technologies are under rapid development. It is already possible to detect deletions, duplications and other chromosomal aberrations of multiple kilobases anywhere in the genome, and the sensitivity of these methods for detecting smaller mutations is improving (Sebat et al, 2004; Sharp et al, 2005). Resequencing tools are increasingly efficient, so large numbers can be screened for rare events in candidate genes first identified by rare, individually detectable events. User-friendly bioinformatics resources now exist to help characterise the structure and function of potential candidate genes. It is increasingly possible to characterise not only mutations in protein coding sequence but also mutations and epigenetic changes in regulatory regions, in non-coding RNA and in transposable elements.
To summarise, we propose that individually rare alleles with large effect, many of which are recent in origin, have a substantial role in causing schizophrenia. Current research designs that focus on collecting large samples of unrelated individuals for analysis of shared alleles or haplotypes are not suitable for detecting such disease alleles. In contrast, rare disease mutations may be revealed by studies of individuals and families that harbour informative genomic events, and by studies of exposed cohorts. A gene harbouring one mutation predisposing to schizophrenia is likely to harbour more than one, with frequencies ranging from relatively common to rare, and effects ranging from modest to severe. To see one is not to see them all.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONTHE HUMAN GENOMEGENETIC HETEROGENEITY IN HUMAN...IMPLICATIONS OF GENETIC...TWO CANDIDATE GENES FOR...IMPLICATIONS FOR GENETIC...ACKNOWLEDGMENTSREFERENCES |
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Blouin, J. L., Dombroski, B. A., Nath, S. K., et al (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nature Genetics, 20, 70-73.[CrossRef][Medline]
Botstein, D. & Risch, N. (2003) Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nature Genetics, 33, 228 -237.
Bray, N. J., Preece, A., Williams, N. M., et al
(2005) Haplotypes at the dystrobrevin binding protein 1
(DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1
expression. Human Molecular Genetics,
14, 1947
-1954.
Brown, A. S., Schaefer, C. A., Wyatt, R. J., et al
(2002) Paternal age and risk of schizophrenia in adult
offspring. American Journal of Psychiatry,
159, 1528
-1533.
Brustowicz, L. M., Hodgkinson, K. A., Chow, E. W., et
al (2000) Location of a major susceptibility locus for
familial schizophrenia on chromosome 1q21-q22.
Science, 288, 678
-682.
Burdick, K. E., Hodgkinson, C. A., Szeszko, P. R., et al (2005) DISC1 and neurocognitive function in schizophrenia. Neuroreport, 16, 1399 -1402.[CrossRef][Medline]
Byrne, M., Agerbo, E., Ewald, H., et al
(2003) Parental age and risk of schizophrenia: a case-control
study. Archives of General Psychiatry,
60, 673
-678.
Callicott, J. H., Straub, R. E., Pezawas, L., et al
(2005) Variation in DISC1 affects hippocampal structure and
function and increases risk for schizophrenia. Proceedings of the
National Academy of Sciences of the United States of America,
102, 8627
-8632.
Cannon, M., Kendell, R., Susser, E., et al (2003) Prenatal and perinatal risk factors for schizophrenia. In The Epidemiology of Schizophrenia (eds R. Murray, P. Jones, E. Susser, et al), pp. 74-100. Cambridge University Press.
Cannon, T. D., Hennah, W., van Erp, T. G., et al
(2005) Association of DISC1/TRAX haplotypes with
schizophrenia, reduced prefrontal gray matter, and impaired short- and
long-term memory. Archives of General Psychiatry,
62, 1205
-1213.
Cavalli-Sforza, L. L., Menozzi, P. & Piazza, A. (1994) History and Geography of Human Genes. Princeton University Press.
Chakravarti, A. (1999) Population genetics – making sense out of sequence. Nature Genetics, 21 (suppl.), 56 -60.[CrossRef][Medline]
Chen, B. E., Sakoda, L. C., Hsing, A. W. et al (2006) Resampling-based multiple hypothesis testing procedures for genetic case-control association studies. Genetic Epidemiology, 30, 495 -507.[CrossRef][Medline]
Cohen, J. C., Kiss, R. S., Pertsemlidis, A., et al
(2004) Multiple rare alleles contribute to low plasma levels
of HDL cholesterol. Science,
305, 869
-872.
Cohen, J. C., Pertsemlidis, A., Fahmi, S., et al
(2006) Multiple rare variants in NPC1L1 associated with
reduced sterol absorption and plasma low-density lipoprotein levels.
Proceedings of the National Academy of Sciences of the United
States of America, 103, 1810
-1815.
Crow, J. F. (2000) The origins, patterns and implications of human spontaneous mutation. Nature Reviews. Genetics, 1, 40 -47.[Medline]
Crow, J. F. (2003) Development: there's
something curious about paternal-age effects. Science,
301, 606
-607.
Dalman, C. & Allebeck, P. (2002) Paternal
age and schizophrenia: further support for an association. American
Journal of Psychiatry, 159, 1591
-1592.
Devon, R. S., Anderson, S., Teague, P. W., et al (2001) Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatric Genetics, 11, 71-78.[CrossRef][Medline]
Ekelund, J., Hovatta, I., Parker, A., et al
(2001) Chromosome 1 loci in Finnish schizophrenia families.
Human Molecular Genetics,
10, 1611
-1617.
El-Saadi, O., Pedersen, C. B., McNeil, T. F., et al (2004) Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia. Schizophrenia Research, 67, 227 -236.[CrossRef][Medline]
Eyre-Walker, A. & Keightley, P. D. (1999) High genomic deleterious mutation rates in hominids. Nature, 397, 344 -347.[CrossRef][Medline]
Fanous, A. H. & Kendler, K. S. (2005) Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Molecular Psychiatry, 10, 6 -13.[CrossRef][Medline]
Fraga, M. F., Ballestar, E., Paz, M. F., et al
(2005) Epigenetic differences arise during the lifetime of
monozygotic twins. Proceedings of the National Academy of Sciences
of the United States of America,
102, 10604
-10609.
Friedman, T. B. & Griffith, A. J. (2003) Human nonsyndromic sensorineural deafness. Annual Review of Genomics and Human Genetics, 4, 341 -402.[CrossRef][Medline]
Funke, B., Finn, C. T., Plocik, A. M., et al (2004) Association of the DTNBP1 locus with schizophrenia in a U.S. population. American Journal of Human Genetics, 75, 891 -898.[CrossRef][Medline]
Goldstein, D. B. & Chikhi, L. (2002) Human migrations and population structure: what we know and why it matters. Annual Review of Genomics and Human Genetics, 3, 129-152[CrossRef][Medline]
Goldstein, D. B., Cavalleri, G. L. & Ahmadi, K. R. (2003) The genetics of common diseases: 10 million times as hard. Cold Spring Harbor Symposia on Quantitative Biology, 68, 395 -402.[CrossRef][Medline]
Gornick, M. C., Addington, A. M., Sporn, A., et al (2005) Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid adjustment scale (PAS). Journal of Autism and Developmental Disorders, 10, 1 -8.[Medline]
Gottesman, I. I. & Shields, J. (1982) Schizophrenia: The Epigenetic Puzzle. Cambridge University Press.
Green, E. K., Norton, N., Peirce, T. et al (2006) Evidence that a DISC1 frame-shift deletion associated with psychosis in a single family may not be a pathogenic mutation. Molecular Psychiatry, 11, 798 -799.[CrossRef][Medline]
Hamshere, M. L., Bennett, P., Williams, N. et al
(2005) Genomewide linkage scan in schizoaffective disorder:
significant evidence for linkage at 1q42 close to DISC1, and suggestive
evidence at 22q11 and 19p13. Archives of General
Psychiatry, 62, 1081
-1088.
Harrison, P. J. & Weinberger, D. R. (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry, 10, 40-68.[CrossRef][Medline]
Haukka, J., Suvisaari, J. & Lonnqvist, J.
(2003) Fertility of patients with schizophrenia, their
siblings, and the general population: a cohort study from 1950 to 1959 in
Finland. American Journal of Psychiatry,
160, 460
-463.
Hennah, W., Varilo, T., Kestila, M., et al
(2003) Haplotype transmission analysis provides evidence of
association for DISC1 to schizophrenia and suggests sex-dependent effects.
Human Molecular Genetics,
12, 3151
-3159.
Hinrichs, A. S., Karolchik, D., Baertsch, R., et al
(2006) The UCSC Genome Browser Database: update 2006.
Nucleic Acids Research,
34, D590
-598.
Hodgkinson, C. A., Goldman, D., Jaeger, J., et al (2004) Disrupted in schizophrenia 1 (DISC1) association with schizophrenia, schizoaffective disorder, and bipolar disorder. American Journal of Human Genetics, 75, 862 -872.[CrossRef][Medline]
International Human Genome Sequencing Consortium (2001a) Initial sequencing and analysis of the human genome. Nature, 409, 860 -921.[CrossRef][Medline]
International Human Genome Sequencing Consortium (2001b) A physical map of the human genome. Nature, 409, 934 -941.[CrossRef][Medline]
International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature, 431, 931 -945.[CrossRef][Medline]
Jaenisch, R. & Bird, A. (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genetics, 33 (suppl.), 245 -254.
Kirov, G., Ivanov, D., Williams, N. M., et al (2004) Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1)and schizophrenia in 488 parent-offspring trios from Bulgaria. Biological Psychiatry, 55, 971 -975.[CrossRef][Medline]
Kockelkorn, T. T., Arai, M., Matsumoto, H., et al (2004) Association study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia. Neuroscience Letters, 368, 41 -45.[CrossRef][Medline]
Kohn, Y., Danilovich, E., Filon, D., et al (2004) Linkage disequilibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 128, 65 -70.[Medline]
Koike, H., Arguello, P. A., Kvajo, M., et al
(2006) Disc1 is mutated in the 129S6/SvEv strain and
modulates working memory in mice. Proceedings of the National
Academy of Sciences of the United States of America,
103, 3693
-3697.
Lewis, S. J., Zammit, S., Gunnell, D., et al (2005) A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 135, 2 -4.[Medline]
Liao, H. M. & Chen, C. H. (2004) Mutation analysis of the human dystrobrevin-binding protein 1 gene in schizophrenicpatients. Schizophrenia Research, 71, 185 -189.[CrossRef][Medline]
Malaspina, D., Corcoran, C. & Fahim, C., et al (2002) Paternal age and sporadic schizophrenia: evidence for de novo mutations. American Journal of Medical Genetics, 114, 299 -303.[CrossRef][Medline]
Maynard, T. M., Haskell, G. T., Lieberman, J. A., et al (2002) 22q11DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome. International Journal of Developmental Neuroscience, 20, 407 -419.[CrossRef][Medline]
McClellan, J. M., Susser, E. & King, M. C.
(2006) Maternal famine, de novo mutations, and schizophrenia.
JAMA, 296, 582
-584.
Meisler, M. H., Kearney, J., Ottman, R., et al (2001) Identification of epilepsy genes in human and mouse. Annual Review of Genetics, 35, 567 -588.[CrossRef][Medline]
Merikangas, K. R. & Risch, N. (2003) Will
the genomics revolution revolutionize psychiatry? American Journal
of Psychiatry, 160, 625
-635.
Millar, J. K., Brown, J., Maule, J. C., et al (1998) A long-range restriction map across 3 Mb of the chromosome 11 breakpoint region of a translocation linked to schizophrenia: localization of the breakpoint and the search for neighbouring genes. Psychiatric Genetics, 8, 175 -181.[Medline]
Millar J. K., Wilson-Annan, J. C., Anderson S., et al
(2000) Disruption of two novel genes by a translocation
co-segregating with schizophrenia. Human Molecular
Genetics, 9, 1415
-1423.
Millar, J. K., Pickard, B. S., Mackie, S., et al
(2005) DISC1 and PDE4B are interacting genetic factors in
schizophrenia that regulate cAMP signaling. Science,
310, 1187
-1191.
Nimgaonkar, V. L. (1998) Reduced fertility in schizophrenia: here to stay? Acta Psychiatrica Scandinavica, 98, 348 -353.[Medline]
Numakawa, T., Yagasaki, Y., Ishimoto, T., et al
(2004) Evidence of novel neuronal functions of dysbindin, a
susceptibility gene for schizophrenia. Human Molecular
Genetics, 13, 2699
-2708.
Owen, M. J., Williams, N. M. & O'Donovan, M. C. (2004) The molecular genetics of schizophrenia new findings promise new insights. Molecular Psychiatry, 9, 14-27.[CrossRef][Medline]
Petit, C., Levilliers, J. & Hardelin, J. P. (2001) Molecular genetics of hearing loss. Annual Review of Genetics, 35, 589 -646.[CrossRef][Medline]
Picker, J. D. & Coyle, J. T. (2005) Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia? Harvard Review of Psychiatry, 13, 197 -205.[CrossRef][Medline]
Risch, N. (1990) Linkage strategies for genetically complex traits. I. Multilocus models. American Journal of Human Genetics, 46, 222 -228.[Medline]
Sachs, N. A., Sawa, A., Holmes, S. E., et al (2005) A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Molecular Psychiatry, 10, 758 -764.[CrossRef][Medline]
Schwab, S. G., Knapp, M., Mondabon, S., et al (2003) Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. American Journal of Human Genetics, 72, 185 -190.[CrossRef][Medline]
Sebat, J., Lakshmi, B., Troge, J., et al
(2004) Large-scale copy number polymorphism in the human
genome. Science, 305, 525
-528.
Sharp, A. J., Locke, D. P., McGrath, S. D., et al (2005) Segmental duplications and copy-number variation in the human genome. American Journal of Human Genetics, 77, 78-88.[CrossRef][Medline]
Sipos, A., Rasmussen, F., Harrison, G., et al
(2004) Paternal age and schizophrenia: a population based
cohort study. BMJ, 329, 1070
.
St Clair, D., Blackwood, D., Muir, W., et al,(1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 336, 13 -16.[CrossRef][Medline]
St Clair, D., Xu, M., Wang, P., et al
(2005) Rates of adult schizophrenia following prenatal
exposure to the Chinese famine of 1959–1961.
JAMA, 294, 557
-562.
Straub, R. E., MacLean, C. J., O'Neill, F. A., et al (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity. Nature Genetics, 11, 287 -293.[CrossRef][Medline]
Straub, R. E., Jiang, Y., MacLean, C. J., et al (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. American Journal of Human Genetics, 71, 337 -348.[CrossRef][Medline]
Susser, E., Neugebauer, R., Hoek, H. W., et al (1996) Schizophrenia after prenatal famine. Further evidence. Archives of General Psychiatry, 53, 25-31.[Abstract]
Tsuchiya, K. J., Takagai, S., Kawai, M., et al (2005) Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337 -342.[CrossRef][Medline]
Vogelstein, B. & Kinzler, K. W. (2004) Cancer genes and the pathways they control. Nature Medicine, 10, 789 -799.[CrossRef][Medline]
Walsh, T., Casadei, S., Coats, K. H., et al
(2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in
families at high risk of breast cancer. JAMA,
295, 1379
-1388
Weickert, C. S., Straub, R. E., McClintock, B. W., et
al (2004) Human dysbindin (DTNBP1) gene expression in
normal brain and in schizophrenic prefrontal cortex and midbrain.
Archives of General Psychiatry,
61, 544
-555.
Williams, N. M., Preece, A., Morris, D. W., et al
(2004) Identification in 2 independent samples of a novel
schizophrenia risk haplotype of the dystrobrevin binding protein gene
(DTNBP1). Archives of General Psychiatry,
61, 336
-344.
Wong, A. H., Gottesman, I. I. & Petronis, A.
(2005) Phenotypic differences in genetically identical
organisms: the epigenetic perspective. Human Molecular
Genetics, 14, R11
-R18.
Zhang, X., Tochigi, M., Ohashi, J., et al (2005) Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population. Schizophrenia Research, 79, 175 -180.[CrossRef][Medline]
Received for publication April 21, 2006. Revision received August 18, 2006. Accepted for publication October 4, 2006.
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