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Chromosomal abnormalities and mental illness


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.


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.


Literature reports of chromosome abnormalities and psychiatric illness were gathered from Medline (1966 to October 2001), the online database of Chromosomal Variation in Man (, 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.


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


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.


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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.

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MacIntyre, D., Blackwood, D., Porteous, D. et al. Chromosomal abnormalities and mental illness. Mol Psychiatry 8, 275–287 (2003).

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

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