Chromosomal abnormalities and mental illness

Abstract

Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

Introduction

While the aetiology of most psychiatric disorders remains obscure, there is convincing evidence (from family, twin and adoption studies) that inherited factors are important in the pathogenesis of both schizophrenia1 and major affective disorder.2 However, it has so far proved difficult to identify these factors, for a variety of reasons. Chromosomal abnormalities in those with mental illness are a valuable resource: they can help us redefine phenotypes, identify candidate genes and refine areas of linkage.3 One difficulty is the uncertain validity of psychiatric diagnoses, despite the use of standardised diagnostic criteria.4,5 The absence of reliable biological or genetic markers specific for schizophrenia or affective disorders continues to call into question the validity of existing classification systems. Linkage to the same chromosomal region has been reported for both schizophrenia and bipolar disorder at several loci, supporting the notion that some genetic risk factors give rise to phenotypes that cross the traditional diagnostic boundaries.6,7 There is also evidence of an overlap between the genetic contributions to depression and anxiety.8

A further difficulty is the lack of clarity as to the mode of inheritance of psychiatric illness, and like other common disorders the inheritance of psychiatric illness is likely to be complex with Mendelian and non-Mendelian subsets.9 An alternative hypothesis proposes that the additive or interactive effects of several genes, each of small effect (the quantitative-trait model), results in the observed phenotype. Indeed, it is likely that genes of small size effect operate.3 This complexity may help explain why the results of linkage studies have sometimes been difficult to interpret. The initial optimism was generated by positive schizophrenia linkage studies,10 and was tempered by lack of independent replication.11 Although it should be possible to achieve statistically robust linkage results using nonparametric (‘model-free’) approaches, such as the affected sib-pair method, the numbers of individuals studied may have to be increased to new and unprecedented levels to achieve adequate power. The most recent genome scans, although not individually generating ‘significant’ results, have shown repeated support for several loci in both schizophrenia12 and bipolar disorder.13 Interestingly, some of these loci appear to be shared by both disorders,14,15 While chromosomal regions may be consistently identified as suggestive of linkage, they are broad genomic regions (20–30 cM) and need to be further refined.

Association studies do not rely on knowledge of the mechanism of transmission of a disorder, can detect genes of small effect, and can identify narrower regions of interest. However, at present, it is impractical to screen the entire genome by association and therefore candidate genes must be selected. Given our limited knowledge of the pathophysiology of mental illness, it is unfortunately possible to construct a hypothesis that almost any brain-expressed sequence may be involved in a mental disorder. In any case, the human genome sequence is in draft form and at present undergoing considerable annotation. It contains numerous small gaps and, although there is preliminary information on gene position and structure, there is little data on predicted function.

Examination of individuals with chromosomal abnormalities and mental illness may be a way of overcoming some of these difficulties. It has been established in many other medical conditions with a genetic basis that chromosomal aberrations, either by direct gene disruption or by positional effects, can produce identical or similar phenotypes to those caused by point mutations and their existence has greatly facilitated the physical mapping and cloning of candidate genes.16,17 Unfortunately, chromosomal analysis is rarely undertaken in adults with psychiatric disorders, unless perhaps they have a concurrent learning disability (this is the UK synonym for mental retardation) or a physical dysmorphism. However, the rate of chromosomal abnormality is substantially increased in those with learning disability, and may be as high as 19% in those with mild learning disability.18 There is a well-described and familial link between schizophrenia and mild learning disability and an increased rate of chromosome abnormalities within this specific population.19 There is also evidence that the schizophrenia may be the primary disorder in this link.20 When a chromosomal abnormality is detected in someone with a psychiatric illness, it may be considered noncoincidental and related to the illness if one or more of the following criteria are met: (a) the chromosomal abnormality is rare and there are independent reports of the abnormality being associated with psychiatric illness; (b) there is colocalisation of the abnormality with a region of suggestive linkage findings; or (c) there is cosegregation of the abnormality with psychiatric illness within the patient's family.3

In a large Scottish family schizophrenia and affective disorder cosegregate with a balanced reciprocal translocation between chromosomes 1 and 11.21 In this pedigree, the linkage between the breakpoint and psychotic illness is highly significant with a Lod score of over 7.0.15 Two brain-expressed genes (DISC1 and DISC2) have been identified as disrupted directly by the chromosome 1 breakpoint.22 As yet, little is known of the function of these genes; however, there is confirmatory linkage from an independent population.23 The strongest evidence for linkage (Lod of 3.2) comes from a marker located within DISC1, making this one of the most likely current candidates for a susceptibility gene for a psychotic disorder.

In a recent study of families near Barcelona with a high prevalence of panic disorder, social phobia and joint laxity, cytogenetic analysis revealed an interstitial duplication of chromosome 15q24–26 co-segregating with illness. Eventually, a Lod score of 5.0 was generated when those with panic disorder, agoraphobia, social phobia and joint laxity were included. These findings were then replicated in 70 unrelated patients: the chromosomal duplication was present in 97% of individuals with panic disorder/agoraphobia but only in 7% of a control group of 189 individuals.24 This is the first strong evidence defining a region of genetic susceptibility for a non-psychotic psychiatric condition that may affect up to 10% of adults at some time in their life.25

Given the uncertain validity of psychiatric diagnoses, the methodological difficulties of linkage and association studies, the proven usefulness of chromosomal aberrations in medical disorders, and the promising findings mentioned above, it seemed that an up-to-date review of reports of chromosomal abnormalities that coexist with psychiatric illness combined with an analysis of associated evidence, supporting or otherwise, was worthwhile. In the few papers published in this area, previous authors have concentrated on schizophrenia, bipolar disorder or the sex chromosomes.26,27,28 This report builds on those studies and takes a broad overview of all chromosomal abnormalities reported in relation to psychiatric illness.

Method

Literature reports of chromosome abnormalities and psychiatric illness were gathered from Medline (1966 to October 2001), the online database of Chromosomal Variation in Man (www.wiley.com/legacy/products/subject/life/borgaonkar/), and from other related reviews.26,27,28 Medline searching used one or the other of the following keywords: affective disorders, bipolar disorder, depression, manic depression, mental disorders, mood disorders, paranoid disorders, psychotic disorders, schizoaffective disorder and schizophrenia; combined with the terms: aneuploidy, chromosome aberrations, chromosome abnormalities, fragile chromosomes and sex chromosomes. Articles in languages other than English without translations were not included. Reports of negative findings were included. Papers that reported patients with learning disability or mental retardation as an additional diagnosis were included, but those with autism alone were excluded.

The presence of a chromosomal abnormality was considered significant if one or more of the following criteria was met: (a) there were reports of independent cases of a rare chromosomal abnormality associated with psychiatric illness; (b) there was colocalisation of the abnormality with a region of positive linkage, or; (c) familial cosegregation of the abnormality with psychiatric illness was demonstrated; when the co-segregation was shown to be statistically significant these were given greater weight.

Results

Table 1 summarises the results of the literature review. Chromosomal loci identified by aberrations that met the criteria mentioned above (several Independent Cases, IC; LinKage support, LK; Co-Segregation, CS; significant Co-Segregation, CS*) are indicated. They, and others of note, are then discussed.

Table 1 Chromosomal rearrangements or anomalies associate with psychiatric disorder

Chromosome 1q

A balanced translocation t(1;11) segregates with major mental illness in a large Scottish family.15 The maximum Lod score (7.1, among the highest ever reported for a psychiatric disorder) was obtained when those with schizophrenia, bipolar disorder or recurrent major depression are classed as affected. Furthermore, schizophrenia linkage studies from Finland generated confirmatory results near the 1q42.1 translocation breakpoint, with Lod scores of 2.6 and 3.7, respectively.29,30 A further study in a Finnish population showed confirmatory linkage (Lod of 3.2) to a marker intragenic to DISC1, a gene disrupted by the translocation.23 Linkage studies of bipolar disorder have suggested evidence of a nearby susceptibility locus at 1q32.31

Chromosome 5q

An unbalanced translocation of the segment 5q11.2–13.3 into 1q32.3, producing a partial trisomy of 5q, segregates with schizophrenia and multiple physical abnormalities in a small pedigree.32 Initial positive linkage findings10 were not replicated.33

In another report, a patient with schizophrenia, dysmorphic features, moderate learning disability and an interstitial deletion at 5q22 was described.34 Two schizophrenia linkage studies35,36 suggest involvement in the region 5q22–31.

Chromosome 7q

A boy with childhood onset schizophrenia, autism and a reciprocal translocation t(1;7)(p22;q21.3) was described.37 Other family members with the translocation displayed language delay, impulsive behaviour and substance abuse. Subsequently, two linkage studies38,39 suggested evidence of schizophrenia susceptibility loci in the 7q21–22 region.

Chromosome 9p

Initial reports in Sweden40,41 and Japan42,43 suggested an increased incidence of the common pericentric inversion, inv(9)(p11q13), in schizophrenic populations; however, this finding has been disputed in Japan44 and has yet to be confirmed in a European population. The inversion is properly considered as a heterochromatic chromosomal variant rather than abnormality and is relatively common in the general population.

Chromosome 9q

Two dysmorphic patients with unusual de novo chromosomal abnormalities affecting the terminal part of 9q were reported: one with schizophrenia and the other with schizoaffective disorder.47,48 Two schizophrenia linkage studies have given modest support for linkage at the terminal breakpoint, 9q34.49,50

Chromosome 10p

Axelsson and Wahlstrom41 reported a case of ‘paranoid psychosis’ in a patient with the rare inversion inv(10)(p12q21). Three schizophrenia linkage studies using different techniques in separate populations have had suggestive results in the 10p12 region.39,51,52 There is also suggestive linkage to this region in bipolar pedigrees.53

Interestingly, there have been case reports of phenocopies of the velo-cardio-facial syndrome (VCFS, also known as Shprintzen Syndrome, DiGeorge Sequence, and 22q11 deletion syndrome; see section Chromosome 22q) associated with interstitial deletions at 10p13.54,55 It should be noted however that psychiatric disorder in these patients has not yet been reported.

Chromosome 11q

A small pedigree in which a t(9;11) translocation cosegregated with affective disorder was described: five translocation carriers had bipolar disorder and one had early onset recurrent depression, leaving only one unaffected carrier.45 Subsequent investigation extended the pedigree and further defined the breakpoints as t(9;11)(p24;q23.1)46 but revealed four unaffected carriers of the translocation, weakening the case for a susceptibility locus at the breakpoints. Linkage studies have not added support to the suggestion of a locus at either breakpoint.12,13 However, very recently, the chromosome 11 breakpoint has been shown to directly disrupt a gene, DIBD1 predicted to code for a brain-expressed mannosyltransferase.126 Initial linkage and linkage disequilibrium analyses in two series of bipolar families, however, was not supportive of a more general role in bipolar disorder.

Chromosome 13q

A small pedigree with an unusual inverted insertion, inv ins(13)(q21.3q32q31), appearing to segregate with psychosis and learning disability was described.56 Significant linkage support for a susceptibility locus at 13q32 has been reported in schizophrenic patients38 and, interestingly, linkage approaching significance (Lod of 3.5) has been generated at the same site in bipolar disorder patients.31

Chromosome 15q

Two interrelated patients with dysmorphisms and the unbalanced derivatives of a reciprocal translocation t(15;18)(q13.3;q22.3), one with bipolar disorder and the other with schizoaffective disorder, were reported.57 Both had partial trisomy of chromosomes 15 and 18. Several schizophrenia linkage studies have given modest support to a susceptibility locus in the region 15q13–14,58,59,60 while others have failed to replicate those findings in separate populations.61,62 Although slightly proximal to the region of highest linkage, the association between Prader–Willi syndrome at 15q11–13 and affective psychotic disorder and especially the recent striking finding of an apparent excess of uniparental disomy cases is noteworthy.63

In a study of families in which an interstitial duplication, dup(15)(q24q26), cosegregated with panic disorder, social phobia, agoraphobia and joint laxity, a Lod score of 5.0 was recorded. In an extension of the original study the duplication was found to be present in 97% of 70 unrelated panic disorder patients but only in 7% of a control group.24

Chromosome 18p

Cross-referencing Danish and Scottish cytogenetic registers revealed two unrelated individuals with the rare pericentric inversion, inv(18)(p11.3q21.1), one with schizophrenia and the other with bipolar disorder.64 There is supportive linkage to the 18p11 region in bipolar disorder31,65 and in schizophrenia.66

Chromosome 18q

At a slightly terminal location to the breakpoint in the two cases mentioned above, a woman with schizoaffective disorder and the translocation t(14;18)(q11.2;q22.1) was reported.67 Two more individuals, one with bipolar disorder and the other with schizoaffective disorder, both with unbalanced derivatives of a translocation t(15;18)(q13.3;q22.3), were described.57 In summary, chromosomal breakpoints at 18q21.1, 18q22.1 and 18q22.3 have been reported. There has been linkage support for the suggestion that susceptibility loci for bipolar disorder68,69,70 and schizophrenia68 reside in the region of 18q21–22.

Chromosome 21

Although the published literature in this area is limited, there is some evidence that individuals with trisomy 21 (Down's syndrome) are at a decreased risk of developing bipolar disorder compared with other learning-disabled individuals or the general population.71,27 This finding could be explained if a major susceptibility locus for bipolar disorder, a recessive disease allele, is present on chromosome 21. A case report of a mother and daughter with chromosome 21p deletion and bipolar disorder72adds some support to the suggestion that this locus might be on 21p. However, most linkage studies73,74,75,76 have indicated that if there is a locus for bipolar disorder on chromosome 21, it lies in the region 21q21.

Chromosome 22q

Initial interest was generated in this region when a paediatric craniofacial surgeon noticed high rates of psychiatric disorder, particularly schizophrenia, in patients with VCFS,77 a condition characterised by distinctive dysmorphology, cardiac abnormalities and associated with small interstitial deletions of chromosome 22q11.2. This deletion has an estimated prevalence of 1 in 4000 live births, making it one of the most common genetic disorders. Further studies have confirmed a high incidence of schizophrenia and bipolar disorder78,79,80 in patients with VCFS and a survey of 100 schizophrenic patients discovered two with previously undiagnosed 22q11 deletions.81 Several studies have reported linkage to markers near the VCFS region in schizophrenia,38,82 and in that area and slightly telomeric to it in bipolar disorder.84,85

Sex chromosome aneuploidy

There have been several studies published in the literature that found an excess of sex chromosome aneuploidies in psychiatric patients. However, these studies were either small or relied on the inaccurate method of sex chromatin screening by buccal smear.28 A Japanese study that reported an excess of X chromosome mosaicism in schizophrenic patients42 was not replicated when an age-matched control group was used.44 The only large-scale study so far cross-checked the Danish Cytogenetic and Psychiatric Central Registers, and found no evidence of increased risk for schizophrenia or bipolar disorder in people with sex chromosome aneuploidies.86 When schizophrenia and bipolar disorder were grouped together, there was evidence, approaching statistical significance, of a decreased risk in those with Turner's syndrome and an increased risk in men with the 47,XYY karyotype. The latter finding is not easily explainable.

Chromosome Xq

A patient with bipolar disorder, learning disability and an unusual translocation t(X;12)(q24;q15) was reported.87 There have been several bipolar studies reporting linkage to markers in the Xq24–27 region;88,89 however, these findings have not been consistently replicated.13

Fragile sites

There are reports of associations between schizophrenia or bipolar disorder and numerous fragile sites (see Table 1); however, none of these have been consistently replicated. Furthermore, except at 1q32, linkage studies have not added support to the suggestion that any of these sites are possible susceptibility loci. It is therefore possible that these fragile sites either represent artefacts or are coincidental findings of no clinical significance.90

Discussion

That there are genetic components to psychiatric disorders is not in question. Eventually, the chromosomal regions harbouring the genes responsible will be identified and then the genes themselves will be cloned. The questions are, which regions and how will the genes be identified?

As the volume of data generated by linkage studies accumulates, several chromosomal loci that are likely to be involved in schizophrenia, and several likely to be involved in bipolar disorder, are emerging. Chromosomal abnormalities have been reported in patients with schizophrenia or bipolar disorder at many of these sites. In two families, genes have already been cloned that are directly disrupted by chromosomal translocations. DISC1 and DISC2 are disrupted at 1q42 in a large Scottish family segregating for schizophrenia and severe affective disorder. As mentioned, there is linkage support for this locus both within this family and from independent studies. In a separate study the gene DIBD1 coding for a mannosyltransferase enzyme has been found disrupted by a translocation involving 11q23 in a family segregating for bipolar disorder.126 However there is, as yet, no further confirmation of its importance. Both these findings are recent and much work still has to be done to identify mutations in other patients with illness. The most likely effect of such direct gene disruption is gene silencing and thus haploinsufficiency. This implies a dosage effect that could be produced by a variety of direct or regulatory dysfunctions in affected individuals without cytogenetic rearrangements. Even if the genes were eventually shown to be risk factors only in the families segregating for the chromosome abnormalities, they will generate new candidates through definition of interacting proteins, for example, by the yeast-2-hybrid method. Another important study has reported an abnormality responsible for nonpsychotic panic disorder and agoraphobia. Provisional susceptibility loci for psychiatric disorders that have been identified by chromosomal abnormalities are summarised in Table 2.

Table 2 Susceptibility loci for psychiatric disorders identified by chromosomal breakpoints

The reports reviewed in the present study support the hypothesis that some genetic susceptibility factors are shared by schizophrenia and bipolar disorder: some families have a chromosomal abnormality that cosegregates with both psychotic and affective disorder;15 some independent cases of rare abnormalities have been reported where one individual has schizophrenia and the other has bipolar disorder;64 and, lastly, patients with similar chromosomal deletions appear to have much increased rates of schizophrenia and bipolar disorder.78 It would therefore seem logical, in the first instance, to concentrate the search for susceptibility loci on those areas that seem to be common to both conditions, using individuals with chromosomal aberrations to help narrow the search. Furthermore, it would seem prudent to attempt to detect chromosomal aberrations in as many of those with psychiatric disorder as possible. It is unrealistic to expect cytogenetic analysis to be performed on all psychiatric patients. However, there are several groups in whom screening for cytogenetic abnormality should be seriously considered, particularly those with (a) strong family histories of psychiatric disorder, (b) mild learning disability or a strong family history of learning disability, or (c) the presence of physical dysmorphisms.

Chromosomal banding studies can quickly locate the gross morphological areas disrupted by chromosomal aberrations.91 Recently, the draft human genome map has become available92,93 and mapping of a set of bacterial artificial chromosome (BAC) clones across the genome has been completed.94 It is therefore possible, using fluorescence in situ hybridisation (FISH), to rapidly define the point in the genome that has been disrupted by a chromosomal aberration, and hence identify candidate genes.

Once candidate regions have been identified, association studies using microsatellite markers or single nucleotide polymorphisms (SNPs) can be used to map chromosome areas in linkage disequilibrium with the causative gene and thereby identify risk haplotypes93,95 including those for psychiatric illness. Once a disease haplotype has been identified, candidate genes in the vicinity can be screened for mutations and the function of the disease gene involved can be further investigated by animal studies. For example, knockout mice have linked the N-methyl-D-aspartate (NMDA) receptor complex to synaptic plasticity, long-term potentiation and memory.96 Complete absence of NMDA receptor expression is not compatible with viability, but those with 5% of normal expression survive to adulthood and display pronounced behavioural abnormalities that resemble some features of the schizophrenic phenotype; these abnormalities are ameliorated by dopaminergic and serotoninergic antagonists that are used to treat schizophrenia, and may indicate that this type of knockout mouse could serve as a useful model for schizophrenia.

In conclusion, chromosomal aberrations have been reported in many of the linkage ‘hot spots’ that are candidate susceptibility loci. If we look for these fortuitous indicators and take advantage of them, using powerful cytogenetic techniques, we can advance our search for the aetiology of psychiatric illness.

References

  1. 1

    McGuffin P, Owen MJ, Farmer AE . Genetic basis of schizophrenia. Lancet 1995; 346: 678–682.

  2. 2

    Craddock N, McGuffin P . Approaches to the genetics of affective disorders. Ann Med 1993; 25: 317–322.

  3. 3

    Evans KL, Muir WJ, Blackwood DH, Porteous DJ . Nuts and bolts of psychiatric genetics: building on the Human Genome Project. Trends Genet 2001; 17: 35–40.

  4. 4

    APA. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association: Washington, DC.

  5. 5

    WHO. The ICD-10 Classification of Mental and Behavioural Disorders. Clinical Descriptions and Diagnostic guidelines. World Health Organisation: Geneva.

  6. 6

    Berrettini WH . Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol Psychiatry 2000; 48: 531–538.

  7. 7

    Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and affective disorder share susceptibility genes? Schizophr Res 1999; 39: 107–111.

  8. 8

    Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . Major depression and generalized anxiety disorder. Same genes, partly different environments? Arch Gen Psychiatry 1992; 49: 716–722.

  9. 9

    McGue M, Gottesman, II . A single dominant gene still cannot account for the transmission of schizophrenia. Arch Gen Psychiatry 1989; 46: 478–480.

  10. 10

    Sherrington R, Brynjolfsson J, Petursson H, Potter M, Dudleston K, Barraclough B et al. Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336: 164–167.

  11. 11

    St Clair D, Blackwood D, Muir W, Baillie D, Hubbard A, Wright A et al. No linkage of chromosome 5q11–q13 markers to schizophrenia in Scottish families. Nature 1989; 339: 305–309.

  12. 12

    Riley BP, McGuffin P . Linkage and associated studies of schizophrenia. Am J Med Genet 2000; 97: 23–44.

  13. 13

    Potash JB, DePaulo Jr JR . Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disorders 2000; 2: 8–26.

  14. 14

    Berrettini WH . Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia. Biol Psychiatry 2000; 47: 245–251.

  15. 15

    Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69: 428–433.

  16. 16

    Collins FS . Positional cloning: let's not call it reverse anymore. Nat Genet 1992; 1: 3–6.

  17. 17

    Collins FS . Positional cloning moves from perditional to traditional. Nat Genet 1995; 9: 347–350.

  18. 18

    Gostason R, Wahlstrom J, Johannisson T, Holmqvist D . Chromosomal aberrations in the mildly mentally retarded. J Ment Defic Res 1991; 35: 240–246.

  19. 19

    Doody GA, Johnstone EC, Sanderson TL, Owens DG, Muir WJ . ‘Pfropfschizophrenie’ revisited. Schizophrenia in people with mild learning disability. Br J Psychiatry 1998; 173: 145–153.

  20. 20

    Sanderson TL, Doody GA, Best J, Owens DG, Johnstone EC . Correlations between clinical and historical variables and cerebral structural variables, in people with mild intellectual disability and schizophrenia. J Intellect Disabil Res 2001; 45: 89–98.

  21. 21

    St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.

  22. 22

    Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

  23. 23

    Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.

  24. 24

    Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J, Peral B et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 2001; 106: 367–379.

  25. 25

    Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG et al. The cross-national epidemiology of panic disorder. Arch Gen Psychiatry 1997; 54: 305–309.

  26. 26

    Bassett ASC, Chow EW, Weksberg R . Chromosomal abnormalities and schizophrenia. Am J Med Genet 2000; 97: 45–51.

  27. 27

    Craddock N, Owen M . Chromosomal aberrations and bipolar affective disorder. Br J Psychiatry 1994; 164: 507–512.

  28. 28

    DeLisi LE, Friedrich U, Wahlstrom J, Boccio-Smith A, Forsman A, Eklund K et al. Schizophrenia and sex chromosome anomalies. Schizophr Bull 1994; 20: 495–505.

  29. 29

    Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD et al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000; 9: 1049–1057.

  30. 30

    Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation,suggesting multiple susceptibility loci. Am J Hum Genet 1999; 65: 1114–1124.

  31. 31

    Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96: 5604–5609.

  32. 32

    Bassett AS, McGillivray BC, Jones BD, Pantzar JT . Partial trisomy chromosome 5 cosegregating with schizophrenia. Lancet 1988; 1: 799–801.

  33. 33

    Aschauer HN, Aschauer-Treiber G, Isenberg KE, Todd RD, Knesevich MA, Garver DL et al. No evidence for linkage between chromosome 5 markers and schizophrenia. Hum Hered 1990; 40: 109–115.

  34. 34

    Bennett RL, Karayiorgou M, Sobin CA, Norwood TH, Kay MA . Identification of an interstitial deletion in an adult female with schizophrenia, mental retardation, and dysmorphic features: further support for a putative schizophrenia-susceptibility locus at 5q21–23.1. Am J Hum Genet 1997; 61: 1450–1454.

  35. 35

    Schwab SG, Eckstein GN, Hallmayer J, Lerer B, Albus M, Borrmann M et al. Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis. Mol Psychiatry 1997; 2: 156–160.

  36. 36

    Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS . Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families. Mol Psychiatry 1997; 2: 148–155.

  37. 37

    Gordon CT, Krasnewich D, White B, Lenane M, Rapoport JL . Brief report: translocation involving chromosomes 1 and 7 in a boy with childhood-onset schizophrenia. J Autism Dev Disor 1994; 24: 537–545.

  38. 38

    Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998; 20: 70–73.

  39. 39

    Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B et al. Genome scan of European–American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. Am J Med Genet 1998; 81: 290–295.

  40. 40

    Axelsson R, Wahlstrom J . Mental disorder and inversion on chromosome 9. Hereditas 1981; 95: 337.

  41. 41

    Axelsson R, Wahlstrom J . Chromosome aberrations in patients with paranoid psychosis. Hereditas 1984; 100: 29–31.

  42. 42

    Kunugi H, Lee KB, Nanko S . Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophr Res 1999; 40: 43–47.

  43. 43

    Nanko S . Schizophrenia with pericentric inversion of chromosome 9: a case report. Jap J Psychiatr Neurol 1993; 47: 47–49.

  44. 44

    Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Meerabux J, Hattori E et al. Karyotype analysis of 161 unrelated schizophrenics: no increased rates of X chromosome mosaicism or inv(9), using ethnically matched and age-stratified controls. Schizophr Res 2001; 52: 171–179.

  45. 45

    Smith M, Wasmuth JJ, McPherson JD . Cosegregation of an 11q22.3–9p22 translocation with affective disorder: proximity of the dopamine D2 receptor gene relative to the translocation breakpoint. Am J Hum Genet 1989; 45: A178.

  46. 46

    Baysal BE, Potkin SG, Farr JE, Higgins MJ, Korcz J, Gollin SM et al. Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree. Am J Med Genet 1998; 81: 81–91.

  47. 47

    Inayama Y, Yoneda H, Fukushima K, Sakai J, Asaba H, Sakai T . Paracentric inversion of chromosome 9 with schizoaffective disorder. Clin Genet 1997; 51: 69–70.

  48. 48

    Park JP, Moeschler JB, Berg SZ, Wurster-Hill DH . Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1). J Med Genet 1991; 28: 282–283.

  49. 49

    Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.

  50. 50

    Riley BP, Tahir E, Rajagopalan S, Mogudi-Carter M, Faure S, Weissenbach J et al. A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families. Psychiatr Genet 1997; 7: 57–74.

  51. 51

    Schwab SG, Hallmayer J, Albus M, Lerer B, Hanses C, Kanyas K et al. Further evidence for a susceptibility locus on chromosome 10p14–p11 in 72 families with schizophrenia by nonparametric linkage analysis. Am J Med Genet 1998; 81: 302–307.

  52. 52

    Straub RE, MacLean CJ, Martin RB, Ma Y, Myakishev MV, Harris-Kerr C et al. A schizophrenia locus may be located in region 10p15–p11. Am J Med Genet 1998; 81: 296–301.

  53. 53

    Foroud T, Castelluccio PF, Koller DL, Edenberg HJ, Miller M, Bowman E et al. Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees. Am J Med Genet 2000; 96: 18–23.

  54. 54

    Daw SC, Taylor C, Kraman M, Call K, Mao J, Schuffenhauer S et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 1996; 13: 458–460.

  55. 55

    Lipson A, Fagan K, Colley A, Colley P, Sholler G, Issacs D et al. Velo-cardio-facial and partial DiGeorge phenotype in a child with interstitial deletion at 10p13—implications for cytogenetics and molecular biology. Am J Med Genet 1996; 65: 304–308.

  56. 56

    Roberts SH, Cowie VA, Singh KR . Intrachromosomal insertion of chromosome 13 in a family with psychosis and mental subnormality. J Ment Defic Res 1986; 30: 227–232.

  57. 57

    Calzolari E, Aiello V, Palazzi P, Sensi A, Calzolari S, Orrico D et al. Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein of 18q22.3. Am J Med Gene 1996; 67: 154–161.

  58. 58

    Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA et al. Linkage disequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001; 105: 20–22.

  59. 59

    Leonard S, Gault J, Moore T, Hopkins J, Robinson M, Olincy A et al. Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative. Am J Med Genet 1998; 81: 308–312.

  60. 60

    Riley BP, Makoff A, Mogudi-Carter M, Jenkins T, Williamson R, Collier D et al. Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. Am J Med Genet 2000; 96: 196–201.

  61. 61

    Curtis L, Blouin JL, Radhakrishna U, Gehrig C, Lasseter VK, Wolyniec P et al. No evidence for linkage between schizophrenia and markers at chromosome 15q13–14. Am J Med Genet 1999; 88: 109–112.

  62. 62

    Neves-Pereira M, Bassett AS, Honer WG, Lang D, King NA, Kennedy JL . No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families. Am J Med Genet 1998; 81: 361–363.

  63. 63

    Boer H, Holland A, Whittington J, Butler J, Webb T, Clarke D . Psychotic illness in people with Prader–Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet 2002; 359: 135–136.

  64. 64

    Mors O, Ewald H, Blackwood D, Muir W . Cytogenetic abnormalities on chromosome 18 associated with bipolar affective disorder or schizophrenia. Br J Psychiatry 1997; 170: 278–280.

  65. 65

    Berrettini WH, Ferraro TN, Goldin LR, Detera-Wadleigh SD, Choi H, Muniec D et al. A linkage study of bipolar illness. Arch Gen Psychiatry 1997; 54: 27–35.

  66. 66

    Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am J Hum Genet 1998; 63: 1139–1152.

  67. 67

    Overhauser J, Berrettini WH, Rojas K . Affective disorder associated with a balanced translocation involving chromosome 14 and 18. Psychiatry Genet 1998; 8: 53–56.

  68. 68

    Maziade M, Roy MA, Rouillard E, Bissonnette L, Fournier JP, Roy A et al. A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes. Mol Psychiatry 2001; 6: 684–693.

  69. 69

    McMahon FJ, Hopkins PJ, Xu J, McInnis MG, Shaw S, Cardon L et al. Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series. Am J Hum Genet 1997; 61: 1397–1404.

  70. 70

    Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet 1995; 57: 1384–1394.

  71. 71

    Collacott RA, Cooper SA, McGrother C . Differential rates of psychiatric disorders in adults with Down's syndrome compared with other mentally handicapped adults. Br J Psychiatry 1992; 161: 671–674.

  72. 72

    el-Badramany MH, Farag TI, al-Awadi SA, Hammad IM, Abdelkader A, Murthy DS . Familial manic-depressive illness with deleted short arm of chromosome 21: coincidental or causal? Br J Psychiatry 1989; 155: 856–857.

  73. 73

    Aita VM, Liu J, Knowles JA, Terwilliger JD, Baltazar R, Grunn A et al. A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet 1999; 64: 210–217.

  74. 74

    Detera-Wadleigh SD, Badner JA, Goldin LR, Berrettini WH, Sanders AR, Rollins DY et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q. Am J Hum Genet 1996; 58: 1279–1285.

  75. 75

    Kwok JB, Adams LJ, Salmon JA, Donald JA, Mitchell PB, Schofield PR . Nonparametric simulation-based statistical analyses for bipolar affective disorder locus on chromosome 21q22.3. Am J Med Genet 1999; 88: 99–102.

  76. 76

    Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nat Genet 1994; 8: 291–296.

  77. 77

    Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW . Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 1992; 42: 141–142.

  78. 78

    Murphy KC, Jones LA, Owen MJ . High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56: 940–945.

  79. 79

    Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R et al. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 1996; 153: 1541–1547.

  80. 80

    Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Mental Dis 1994; 182: 476–478.

  81. 81

    Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995; 92: 7612–7616.

  82. 82

    Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J et al. A genome-wide search for schizophrenia susceptibility genes. Am J Med Genet 1998; 81: 364–376.

  83. 83

    Garver DL, Holcomb J, Mapua FM, Wilson R, Barnes B . Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees. Schizophr Res 2001; 52: 145–160.

  84. 84

    Edenberg HJ, Foroud T, Conneally PM, Sorbel JJ, Carr K, Crose C et al. Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17 and 22. Am J Med Genet 1997; 74: 238–246.

  85. 85

    Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA et al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001; 98: 585–590.

  86. 86

    Mors O, Mortensen PB, Ewald H . No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes. Psycholog Med 2001; 31: 425–430.

  87. 87

    Eshkevari HS . Translocation of chromosome Xq24 to chromosome 12q15[46, X, t(X;12)(q24;q15)] its association with bipolar affective disorder and mental retardation; first report of a new chromosomal abnormality. Am J Med Genet 1997; 74: 607 (Abst).

  88. 88

    Lucotte G, Landoulsi A, Berriche S, David F, Babron MC . Manic depressive illness is linked to factor IX in a French pedigree. Ann Genet 1992; 35: 93–95.

  89. 89

    Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L . Evidence of a predisposing locus to bipolar disorder on Xq24–q27.1 in an extended Finnish pedigree. Genome Res 1995; 5: 105–115.

  90. 90

    Sutherland GR, Baker E . The clinical significance of fragile sites on human chromosomes. Clin Genet 2000; 58: 157–161.

  91. 91

    Caspersson T, Farber S, Foley GE, Kudynowski J, Modest EJ, Simonsson E et al. Chemical differentiation along metaphase chromosomes. Exp Cell Res 1968; 49: 219–222.

  92. 92

    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

  93. 93

    Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES . High-resolution haplotype structure in the human genome. Nat Genet 2001; 29: 229–232.

  94. 94

    Cheung VG, Nowak N, Jang W, Kirsch IR, Zhao S, Chen XN et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 2001; 409: 953–958.

  95. 95

    Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.

  96. 96

    Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998; 396: 433–439.

  97. 97

    Fananas L, Fuster C, Guillamat R, Miro R . Chromosomal fragile site 1q21 in schizophrenic patients. Am J Psychiatry 1997; 154: 716.

  98. 98

    Turecki G, Smith M, Mari JJ . Type I bipolar disorder associated with a fragile site on chromosome 1. Am J Med Genet 1995; 60: 179–182.

  99. 99

    Maziade M, Debraekeleer M, Genest P, Cliche D, Fournier JP, Garneau Y et al. A balanced 2:18 translocation and familial schizophrenia: falling short of an association. Arch Gen Psychiatry 1993; 50: 73–75.

  100. 100

    Glass IA, Stormer P, Oei PT, Hacking E, Cotter PD . Trisomy 2q11.2→q21.1 resulting from an unbalanced insertion in two generations. J Med Genet 1998; 35: 319–322.

  101. 101

    Rudduck C, Franzen G . A new heritable fragile site on human chromosome 3. Hereditas 1983; 98: 297–299.

  102. 102

    Palmour RM, Miller S, Fielding A, Vekemans M, Ervin FR . A contribution to the differential diagnosis of the ‘group of schizophrenias’: structural abnormality of chromosome 4. J Psychiatry Neurosci 1994; 19: 270–277.

  103. 103

    Malaspina D, Warburton D, Amador X, Harris M, Kaufmann CA . Association of schizophrenia and partial trisomy of chromosome 5p.A case report. Schizophr Res 1992; 7: 191–196.

  104. 104

    Holland T, Gosden C . A balanced chromosomal translocation partially co-segregating with psychotic illness in a family. Psychiatr Res 1990; 32: 1–8.

  105. 105

    Price WH, Brunton M, Buckton K, Jacobs PA . Chromosome survey of new patients admitted to the four maximum security hospitals in the United Kingdom. Clin Genet 1976; 9: 389–398.

  106. 106

    Sperber MA . Schizophrenia and organic brain syndrome with trisomy 8 (group-C trisomy 8 [47, XX, 8+]). Biol Psychiatry 1975; 10: 27–43.

  107. 107

    Garofalo G, Ragusa RM, Argiolas A, Scavuzzo C, Spina E, Barletta C . Evidence of chromosomal fragile sites in schizophrenic patients. Ann Genetique 1993; 36: 132–135.

  108. 108

    Escobar JI . A cytogenetic study of children with psychiatric disorders. Comprehensive Psychiatry 1976; 17: 309–313.

  109. 109

    Nielsen J, Hreidarsson AB, Christensen KR . D–D translocations in patients with mental illness. Hereditas 1973; 75: 131–135.

  110. 110

    Clarke DJ . Prader–Willi syndrome and psychoses. Br J Psychiatry 1993; 163: 680–684.

  111. 111

    Kerbeshian J, Burd L, Randall T, Martsolf J, Jalal S . Autism, profound mental retardation and atypical bipolar disorder in a 33-year-old female with a deletion of 15q12. J Ment Defic Res 1990; 34: 205–210.

  112. 112

    Kerbeshian J, Severud R, Burd L, Larson L . Peek-a-boo fragile site at 16d associated with Tourette syndrome, bipolar disorder, autistic disorder and mental retardation. Am J Med Genet 2000; 96: 69–73.

  113. 113

    Christensen KR, Friedrich U, Jacobsen P, Jensen K, Nielsen J, Tsuboi T . Ring chromosome 18 in mother and daughter. J Ment Defic Res 1970; 14: 49–67.

  114. 114

    Smith AB, Peterson P, Wieland J, Moriarty T, DeLisi LE . Chromosome 18 translocation (18;21) (p11.1;p11.1) associated with psychosis in one family. Am J Med Genet 1996; 67: 560–563.

  115. 115

    Chodirker BN, Chudley AE, Ray M, Wickstrom DE, Riordan DL . Fragile 19p13 in a family with mental illness. Clin Genet 1987; 31: 1–6.

  116. 116

    Cooper SA, Collacott RA . Mania and Down's syndrome. Br J Psychiatry 1993; 162: 739–743.

  117. 117

    Craddock N, Owen M . Is there an inverse relationship between Down's syndrome and bipolar affective disorder? Literature review and genetic implications. J Intellect Disabil Res 1994; 38: 613–620.

  118. 118

    Myers BA, Pueschel SM . Major depression in a small group of adults with Down syndrome. Res Dev Disabil 1995; 16: 285–299.

  119. 119

    Panzer MJ, Tandon R . Bipolar disorder associated with Turner's syndrome. J Nerv Ment Dis 1991; 179: 702.

  120. 120

    Woodhouse WJ, Holland AJ, McLean G, Reveley AM . The association between triple X and psychosis. Br J Psychiatry 1992; 160: 554–557.

  121. 121

    Kawanishi C, Kono M, Onishi H, Ishii N, Ishii K . A case of Turner syndrome with schizophrenia: genetic relationship between Turner syndrome and psychosis. Psychiatry Clin Neurosci 1997; 51: 83–85.

  122. 122

    Prior TI, Chue PS, Tibbo P . Investigation of Turner syndrome in schizophrenia. Am J Med Genet 2000; 96: 373–378.

  123. 123

    Nanko S . Schizophrenia-like psychosis in a 46,XX male. Folia Psychiatr Neurol Jpn 1981; 35: 461–463.

  124. 124

    Rajagopalan M, MacBeth R, Varma SL . XYY chromosome anomaly and schizophrenia. Am J Med Genet 1998; 81: 64–65.

  125. 125

    Deckert J, Strik WK, Fritze J . Organic schizophrenic syndrome associated with symmetrical basal ganglia sclerosis and XO/XY-mosaic. Biol Psychiatry 1992; 31: 401–403.

  126. 126

    Baysal BE, Willett-Brozick JE, Badner JA, Corona W, Ferrell RE, Nimgaonkar VL et al. A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family. Neurogenetics 2002; 4: 43–53.

Download references

Acknowledgements

DJ MacIntyre was a research registrar supported by the Wellcome Trust. WJ Muir, D Blackwood and DJ Porteous were in support of grant funding from the Scottish Executive, the Medical Research council. The authors would also like to thank Dr Judy Fantes, MRC Human Genetics Unit, Edinburgh for her helpful comments on the manuscript.

Author information

Correspondence to W J Muir.

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • schizophrenia
  • bipolar disorder
  • chromosomes
  • linkage
  • mental retardation
  • learning disability

Further reading