Molecular Psychiatry (2003) 8, 275–287 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp FEATURE ARTICLE Chromosomal abnormalities and mental illness DJ MacIntyre1, DHR Blackwood1,2, DJ Porteous2, BS Pickard1,2 and WJ Muir1,2 1Department of Psychiatry, University of Edinburgh, Edinburgh, Scotland, UK; 2Department of Medical Sciences, University of Edinburgh, Edinburgh, Scotland, UK

Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative 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 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 . 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. Molecular Psychiatry (2003) 8, 275–287. doi:10.1038/sj.mp.4001232 Keywords: schizophrenia; bipolar disorder; ; linkage; mental retardation; learning disability

Introduction of an overlap between the genetic contributions to depression and anxiety.8 While the aetiology of most psychiatric disorders A further difficulty is the lack of clarity as to the remains obscure, there is convincing evidence (from mode of inheritance of psychiatric illness, and like family, and adoption studies) that inherited other common disorders the inheritance of psychia- factors are important in the pathogenesis of both tric illness is likely to be complex with Mendelian schizophrenia1 and major affective disorder.2 How- and non-Mendelian subsets.9 An alternative hypoth- ever, it has so far proved difficult to identify these esis proposes that the additive or interactive effects of factors, for a variety of reasons. Chromosomal several genes, each of small effect (the quantitative- abnormalities in those with mental illness are a trait model), results in the observed phenotype. valuable resource: they can help us redefine pheno- Indeed, it is likely that genes of small size effect types, identify candidate genes and refine areas of operate.3 This complexity may help explain why the linkage.3 One difficulty is the uncertain validity of results of linkage studies have sometimes been psychiatric diagnoses, despite the use of standardised difficult to interpret. The initial optimism was diagnostic criteria.4,5 The absence of reliable biologi- generated by positive schizophrenia linkage studies,10 cal or genetic markers specific for schizophrenia or and was tempered by lack of independent replica- affective disorders continues to call into question the tion.11 Although it should be possible to achieve validity of existing classification systems. Linkage to statistically robust linkage results using nonpara- the same chromosomal region has been reported for metric (‘model-free’) approaches, such as the affected both schizophrenia and bipolar disorder at several sib-pair method, the numbers of individuals studied loci, supporting the notion that some genetic risk may have to be increased to new and unprecedented factors give rise to phenotypes that cross the tradi- levels to achieve adequate power. The most recent tional diagnostic boundaries.6,7 There is also evidence genome scans, although not individually generating ‘significant’ results, have shown repeated support for Correspondence: Dr Walter J Muir, Department of Psychiatry, several loci in both schizophrenia12 and bipolar University of Edinburgh, Kennedy Tower, Royal Edinburgh disorder.13 Interestingly, some of these loci appear to Hospital, Morningside Park, Edinburgh EH10 5HF, Scotland, UK. 14,15 E-mail: [email protected] be shared by both disorders, While chromosomal Received 6 May 2002; revised 10 May 2002; accepted 11 July 2002 regions may be consistently identified as suggestive of abnormalities and mental illness DJ MacIntyre et al 276 linkage, they are broad genomic regions (B20–30 cM) for linkage (Lod of 3.2) comes from a marker located and need to be further refined. within DISC1, making this one of the most likely Association studies do not rely on knowledge of the current candidates for a susceptibility gene for a mechanism of transmission of a disorder, can detect psychotic disorder. genes of small effect, and can identify narrower In a recent study of families near Barcelona with a regions of interest. However, at present, it is imprac- high prevalence of panic disorder, social phobia and tical to screen the entire genome by association and joint laxity, cytogenetic analysis revealed an inter- therefore candidate genes must be selected. Given our stitial duplication of chromosome 15q24–26 co- limited knowledge of the pathophysiology of mental segregating with illness. Eventually, a Lod score of illness, it is unfortunately possible to construct a 5.0 was generated when those with panic disorder, hypothesis that almost any brain-expressed sequence agoraphobia, social phobia and joint laxity were may be involved in a mental disorder. In any case, the included. These findings were then replicated in 70 sequence is in draft form and at unrelated patients: the chromosomal duplication was present undergoing considerable annotation. It con- present in 97% of individuals with panic disorder/ tains numerous small gaps and, although there is agoraphobia but only in 7% of a control group of 189 preliminary information on gene position and struc- individuals.24 This is the first strong evidence defin- ture, there is little data on predicted function. ing a region of genetic susceptibility for a non- Examination of individuals with chromosomal psychotic psychiatric condition that may affect up abnormalities and mental illness may be a way of to 10% of adults at some time in their life.25 overcoming some of these difficulties. It has been Given the uncertain validity of psychiatric diag- established in many other medical conditions with a noses, the methodological difficulties of linkage and genetic basis that chromosomal aberrations, either by association studies, the proven usefulness of chromo- direct gene disruption or by positional effects, can somal aberrations in medical disorders, and the produce identical or similar phenotypes to those promising findings mentioned above, it seemed that caused by point mutations and their existence has an up-to-date review of reports of chromosomal greatly facilitated the physical mapping and cloning abnormalities that coexist with psychiatric illness of candidate genes.16,17 Unfortunately, chromosomal combined with an analysis of associated evidence, analysis is rarely undertaken in adults with psychia- supporting or otherwise, was worthwhile. In the few tric disorders, unless perhaps they have a concurrent papers published in this area, previous authors have learning disability (this is the UK synonym for mental concentrated on schizophrenia, bipolar disorder or retardation) or a physical dysmorphism. However, the the sex chromosomes.26–28 This report builds on those rate of chromosomal abnormality is substantially studies and takes a broad overview of all chromoso- increased in those with learning disability, and may mal abnormalities reported in relation to psychiatric be as high as 19% in those with mild learning illness. disability.18 There is a well-described and familial link between schizophrenia and mild learning dis- Method ability and an increased rate of chromosome abnorm- alities within this specific population.19 There is also Literature reports of chromosome abnormalities and evidence that the schizophrenia may be the primary psychiatric illness were gathered from Medline (1966 disorder in this link.20 When a chromosomal abnorm- to October 2001), the online database of Chromosomal ality is detected in someone with a psychiatric illness, Variation in Man (www.wiley.com/legacy/products/ it may be considered noncoincidental and related to subject/life/borgaonkar/), and from other related re- the illness if one or more of the following criteria are views.26–28 Medline searching used one or the other of met: (a) the chromosomal abnormality is rare and the following keywords: affective disorders, bipolar there are independent reports of the abnormality disorder, depression, manic depression, mental dis- being associated with psychiatric illness; (b) there is orders, mood disorders, paranoid disorders, psychotic colocalisation of the abnormality with a region of disorders, schizoaffective disorder and schizophre- suggestive linkage findings; or (c) there is cosegrega- nia; combined with the terms: , chromo- tion of the abnormality with psychiatric illness some aberrations, chromosome abnormalities, fragile within the patient’s family.3 chromosomes and sex chromosomes. Articles in In a large Scottish family schizophrenia and languages other than English without translations affective disorder cosegregate with a balanced reci- were not included. Reports of negative findings were procal translocation between chromosomes 1 and included. Papers that reported patients with learning 11.21 In this pedigree, the linkage between the break- disability or mental retardation as an additional point and psychotic illness is highly significant with diagnosis were included, but those with alone a Lod score of over 7.0.15 Two brain-expressed genes were excluded. (DISC1 and DISC2) have been identified as disrupted The presence of a chromosomal abnormality was directly by the breakpoint.22 As yet, considered significant if one or more of the following little is known of the function of these genes; criteria was met: (a) there were reports of independent however, there is confirmatory linkage from an cases of a rare chromosomal abnormality associated independent population.23 The strongest evidence with psychiatric illness; (b) there was colocalisation

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 277 of the abnormality with a region of positive linkage, heterochromatic chromosomal variant rather than or; (c) familial cosegregation of the abnormality with abnormality and is relatively common in the general psychiatric illness was demonstrated; when the co- population. segregation was shown to be statistically significant these were given greater weight. Chromosome 9q Two dysmorphic patients with unusual de novo Results chromosomal abnormalities affecting the terminal part of 9q were reported: one with schizophrenia Table 1 summarises the results of the literature and the other with schizoaffective disorder.47,48 Two review. Chromosomal loci identified by aberrations schizophrenia linkage studies have given modest that met the criteria mentioned above (several support for linkage at the terminal breakpoint, Independent Cases, IC; LinKage support, LK; Co- 9q34.49,50 Segregation, CS; significant Co-Segregation, CS*) are indicated. They, and others of note, are then dis- cussed. Chromosome 10p Axelsson and Wahlstrom41 reported a case of ‘para- Chromosome 1q noid psychosis’ in a patient with the rare inversion A balanced translocation t(1;11) segregates with major inv(10)(p12q21). Three schizophrenia linkage studies mental illness in a large Scottish family.15 The using different techniques in separate populations maximum Lod score (7.1, among the highest ever have had suggestive results in the 10p12 region.39,51,52 reported for a psychiatric disorder) was obtained There is also suggestive linkage to this region in when those with schizophrenia, bipolar disorder or bipolar pedigrees.53 recurrent major depression are classed as affected. Interestingly, there have been case reports of Furthermore, schizophrenia linkage studies from phenocopies of the velo-cardio-facial syndrome Finland generated confirmatory results near the (VCFS, also known as Shprintzen Syndrome, Di- 1q42.1 translocation breakpoint, with Lod scores of George Sequence, and 22q11 syndrome; see 2.6 and 3.7, respectively.29,30 A further study in a section Chromosome 22q) associated with interstitial Finnish population showed confirmatory linkage deletions at 10p13.54,55 It should be noted however (Lod of 3.2) to a marker intragenic to DISC1, a gene that psychiatric disorder in these patients has not yet disrupted by the translocation.23 Linkage studies of been reported. bipolar disorder have suggested evidence of a nearby 31 susceptibility locus at 1q32. Chromosome 11q A small pedigree in which a t(9;11) translocation Chromosome 5q cosegregated with affective disorder was described: An unbalanced translocation of the segment 5q11.2– five translocation carriers had bipolar disorder and 13.3 into 1q32.3, producing a partial of 5q, one had early onset recurrent depression, leaving segregates with schizophrenia and multiple physical only one unaffected carrier.45 Subsequent investiga- abnormalities in a small pedigree.32 Initial positive 10 33 tion extended the pedigree and further defined the linkage findings were not replicated. breakpoints as t(9;11)(p24;q23.1)46 but revealed four In another report, a patient with schizophrenia, unaffected carriers of the translocation, weakening dysmorphic features, moderate learning disability the case for a susceptibility locus at the breakpoints. and an interstitial deletion at 5q22 was described.34 35,36 Linkage studies have not added support to the Two schizophrenia linkage studies suggest invol- suggestion of a locus at either breakpoint.12,13 How- vement in the region 5q22–31. ever, very recently, the breakpoint has been shown to directly disrupt a gene, DIBD1 Chromosome 7q predicted to code for a brain-expressed mannosyl- A boy with childhood onset schizophrenia, autism transferase.126 Initial linkage and linkage disequili- and a reciprocal translocation t(1;7)(p22;q21.3) was brium analyses in two series of bipolar families, described.37 Other family members with the translo- however, was not supportive of a more general role in cation displayed language delay, impulsive behaviour bipolar disorder. and substance abuse. Subsequently, two linkage studies38,39 suggested evidence of schizophrenia sus- ceptibility loci in the 7q21–22 region. Chromosome 13q A small pedigree with an unusual inverted , Chromosome 9p inv ins(13)(q21.3q32q31), appearing to segregate with Initial reports in Sweden40,41 and Japan42,43 suggested psychosis and learning disability was described.56 an increased incidence of the common pericentric Significant linkage support for a susceptibility locus inversion, inv(9)(p11q13), in schizophrenic popula- at 13q32 has been reported in schizophrenic pa- tions; however, this finding has been disputed in tients38 and, interestingly, linkage approaching sig- Japan44 and has yet to be confirmed in a European nificance (Lod of 3.5) has been generated at the same population. The inversion is properly considered as a site in bipolar disorder patients.31

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 278 Table 1 Chromosomal rearrangements or anomalies associate with psychiatric disorder

Site Abnormality Diagnosis Comments CM Reference

1p22 See 7q21.3 1q21 Fragile site 7 of 19 schizophrenic patients 97 screened; number of controls affected is not stated 1q32 Fragile site Bipolar disorder 4 of 10 bipolar patients tested LK 98 1q32.3 See 5q11.2 1q42 Reciprocal translocation, Schizophrenia, bipolar Translocation segregating LK/ 15, 21 t(1;11)(q42;q14.3) disorder and recurrent through 5 generations Lod CS* major depression score highest (7.1) when individuals with schizophrenia, bipolar disorder or major depression are considered affected 2 Complex abnormality, Schizophrenia and learning One case 19 inversion and reciprocal disability translocation involving chromosomes 2 and 11 2p11.2 reciprocal translocation, Schizophrenia One case, translocation not 99 t(2;18)(p11.2;q11.2) segregating with illness 2q11.2 Insertion, insertion of Schizoaffective disorder, Mother with schizoaffective 100 2q11.2–q21.1 into 8p21.3 psychotic illness and disorder and borderline leading to a learning disability learning disability; daughter partial trisomy of 2q had psychotic episode, was dysmorphic and had learning disability 3p21 Fragile site Schizophrenia 2 sib pairs with illness and 2 101 others. Mother with fragile site and 2 affected children, well herself 4p15.2 Inversion, inv(4)(p15.2q21.3) Schizophrenia One case of schizophrenia. 102 Proband’s mother had inversion and schizotypic traits 4q21.3 see 4p15.2 5p13 Reciprocal translocation, Paranoid psychosis One case 41 t(5;6)(p13;q15) 5p14.1 Unbalanced translocated Schizophrenia One case of schizophrenia; 103 segment from 5p14.1 into sibling with translocation had 14q32.3 leading to a partial severe epilepsy trisomy of 5p 5q11.2 Unbalanced translocated Schizophrenia Partial trisomy segregating CS 32 segment 5q11.2–13.3 into 1q with schizophrenia and leading to a partial trisomy multiple physical of 5q abnormalities 5q22 Interstitial deletion, Schizophrenia and mild One case LK 34 del(5)(q22q23.3) learning disability 6q14.2 Reciprocal translocation, Schizoaffective disorder and 2 carriers psychotic, 2 suicidal 104 t(6;11)(q14.2;q25) mild learning disability while 2 carriers unaffected 6q15 See 5p13 7p12 Reciprocal translocation, Schizophrenia Inherited translocation; 105 t(7;8)(p12;p23) other family members with translocation were well 7q21.3 Reciprocal translocation, Schizophrenia One case; LK 37 t(1;7)(p22;q21.3) (childhood onset), autism other translocation and learning disability carriers displayed paranoid traits, language delay and substance abuse 8 trisomy Schizophrenia and ‘organic One case; other family 106 brain syndrome’ members not karyotyped 8p21.3 See 2q11.2 8p23 See 7p12

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 279 Table 1 (continued)

Site Abnormality Diagnosis Comments CM Reference

8q24 Fragile site Schizophrenia 50 schizophrenic patients 107 screened. 36% showed fragility vs 6% of controls 9p11 Pericentric inversion, (a) Paranoid psychosis In 13 of 134 patients 41 inv(9)(p11q13) (b) Schizophrenia Mother and son both affected 43 (c) Schizophrenia and One case 19 learning disability (d) Schizophrenia Incidence of inv 9 double 42 population rate in 250 schizophrenic patients. These inversions are generally regarded as heterochromatic variants 9p12 Pericentric inversion, (e) Schizophrenia Incidence of inv 9 same as 44 inv(9)(p12q13) Probably population rate same inversion as above 9p21 Fragile site Schizophrenia 50 schizophrenic patients 107 screened. 82% showed fragility while found in 8% of controls 9p24 see 11q23.1 9q31.2 De novo paracentric inversion, Schizoaffective disorder One case, dysmorphisms IC/LK 47 inv(9)(q31.2q34.3) present 9q32 Interstitial deletion, Schizophrenia and learning One case, dysmorphisms IC/LK 48 del(9)(q32q34.1) disability present 10p12 Inversion, inv(10)(p12q21) Paranoid psychosis One case LK 41 11 See 2 11q14.3 See 1q42 11q23.1 Reciprocal translocation, Bipolar disorder, unipolar Of 11 carriers, 5 had bipolar CS 46, 126 t(9;11)(p24;q23.1) depression disorder and 1 had unipolar disorder Chromosome 11 breakpoint directly disrupts a candidate gene DIBD1 11q23.3 Partial trisomy 11, Recurrent major depression De novo duplication but family 27 dup(11)(q23.3q25) and moderate learning history of depression from both disability parents 11q25 See 6q14.2 12q15 See Xq24 13 Reciprocal translocation, (a) Schizophrenia and One case from a survey of 30 108 t(13;14) borderline learning disability child psychiatry in-patients (b) Schizophrenia and Inherited translocation not co- 105 learning disability segregating. These are examples of the very common Robertsonian translocation which are probably best regarded as non-significant variants 13q13 Reciprocal translocation, Depression One patient in series Prob. 109 t(13;14) Robertsonian translocation as above 13q21.3 Inversion and insertion, inv Psychosis and learning 3 of four carriers had learning 56 ins(13)(q21.3q32q31) disability disability, of whom two had psychosis 13q32 See 13q21 14q11.2 See 18q22.1 14q14 See 13q13 14q32.3 See 5p14.1 15q11 (a) Deletion, del(15)(q11q13) Psychosis and learning 3 cases of psychosis 110 disability accompanying Prader–Willi syndrome (b) of Severe affective disorder 7 of 28 adult cases of Prader– 63 with psychotic features and Willi syndrome had psychotic learning disability affective illness; 5 had

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 280 Table 1 (continued)

Site Abnormality Diagnosis Comments CM Reference

uniparental disomy, one had a deletion and another an imprinting centre 15q12 Deletion, del(15)q12 Atypical bipolar disorder, One case, no family history 111 autism and severe learning disability 15q13.3 Partial unbalanced derivatives Bipolar disorder and Two related individuals with LK 57 leading to partial trisomy 15q schizoaffective disorder dysmorphisms, one with and 18q stemming from a bipolar disorder had 15q reciprocal translocation partial trisomy and one with t(15;18)(q13.3;q22.3)s schizoaffective disorder had 18q partial trisomy 15q24 Interstitial duplication, Panic disorder, agoraphobia, Duplication segregating CS* 24 dup(15)(q24q26) social phobia, simple phobia through 7 families; Lod score and joint laxity highest (5.0) when individuals with panic disorder, agoraphobia, social phobia and joint laxity are considered affected 16q22 Fragile site Bipolar disorder, Tourette Fragile sites not replicated at 112 syndrome and learning later date disability 17p12 Fragile site Paranoid psychosis In 4 of 134 psychotic 41 patients 18p11 Manic-depressive psychosis Mother and daughter with 113 r(18)(p11q23) and learning disability illness and ring chromosome; father schizophrenic 18p11.1 (a) Derivatives of a t(18;21) Schizophrenia and mild One individual with 114 translocation resulting in learning disability schizophrenia, learning del(18)(p11.1pter) and disability and dysmorphic dup(21)(p11.1pter) features. Twin (believed to be normal) unavailable for analysis (b) Reciprocal translocation Schizophrenia, psychotic Two brothers and mother of (a), t(18;21)(p11.1;p11.1) episodes and paranoid traits all with balanced translocation and schizophrenia, paranoid traits and psychotic episodes, respectively 18p11.3 Pericentric inversion, Schizophrenia and bipolar One case with schizophrenia IC/LK 64 inv(18)(p11.3q21.1) disorder in Scotland; one case with bipolar disorder in Denmark 18q11.2 See 2p11.2 18q21.1 See 18p11.3 IC/LK 18q22.1 Reciprocal translocation Schizoaffective disorder One case LK 67 t(14;18)(q11.2;q22.1) 18q22.3 See15q13.3 19p13 Fragile site Schizophrenia, autism and Monozygotic twin brothers; 115 learning disability one with schizophrenia, one with autism and learning disability. One further brother with schizophrenia, another unaffected 21 Trisomy (a) Depression Higher rates of unipolar 71 disorder and lower rates of bipolar disorder than in other patients with learning disability (b) Bipolar disorder Reviews 6 cases of bipolar 116 disorder and one case of unipolar mania in individuals with trisomy 21

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 281 Table 1 (continued)

Site Abnormality Diagnosis Comments CM Reference

(c) Bipolar and unipolar Review of literature suggesting 117 disorder increased rates of depression and decreased rates of bipolar disorder (d) Depression depression at population rate 118 in 164 patients 21p Deletion, del(21)(p11) Bipolar disorder Mother and daughter with 72 deletion and illness However, possibly a short arm variant 21p11.1 See 18p11.1 22q11 Interstitial deletion (a) Schizophrenia with In 12 of 90 patients with IC/LK 77 paranoid delusions clinical VCFS (b) Schizophrenia and In 4 of 14 subjects with IC/LK 80 schizoaffective disorder clinical VCFS (c) Bipolar disorder, (i) 7 children with bipolar II IC/LK 79 schizoaffective disorder, disorder out of 15 aged 5–16 depression and dysthymia (ii) 10 adults, of which 6 with bipolar I or II, two with schizoaffective disorder, one with major depression and one with dysthymia (d) Schizophrenia, bipolar 50 adults with VCFS:15 IC/LK 78 disorder and depression psychotic including 12 schizophrenic, 1 schizo- affective and 1 bipolar. 6 with unipolar disorder X 45,X/46,X iso(Xq) mosaic Bipolar disorder Case report 119 45,X/46,XX mosaics, also Schizophrenia Survey of schizophrenic 28 47,XXX, 47XXY patients and review of multiple studies. 4 of 77 female schizophrenic patients had X/XX chromosome mosaicism. Small increased incidence of 47,XXX and 47,XXY in schizophrenic populations 47,XXX Schizophrenia and One case of each 120 schizoaffective disorder 45,X; 47,XXX; 47,XXY Schizophrenia or bipolar Danish psychiatric and 86 disorder cytogenetic registers were cross-checked. There was a nearly significant decrease in incidence of illness with 45,X: while there was no association of illness with 47,XXX or 47,XXY 45,X/46,XX mosaic and Schizophrenia From a sample of 250 patients, 42 47,XXY 3 with mosaic karyotypes and 2 patients with 47,XXY were detected 45,X/46,XX mosaic Schizophrenia One case with schizophrenia 121 and mosaicism; daughter with schizophrenia but normal chromosomes 45,X/46XX mosaic Schizophrenia 2 cases of mosaic X/XX 122 described. Literature review suggesting 11 cases of X/XX mosaicism in 6483 schizophrenic women Xp22.33 46, X, t(X;Y)(p22.33;p11.2) Schizophrenia-like psychosis involves insertion of 123 Y material into

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 282 Table 1 (continued)

Site Abnormality Diagnosis Comments CM Reference

Xq24 reciprocal translocation, Bipolar disorder and learning One case LK 87 t(X;12)(q24;q15) disability Y 47,XYY Schizophrenia One case 124 45,X/46,XY mosaic Schizophrenia Multiple urogenital and 125 neurological abnormalities 47,XYY Schizophrenia or Bipolar Danish psychiatric and 86 disorder cytogenetic registers were cross-checked. There was a nearly significant increase in incidence of illness with 47,XYY Yp11.2 See Xq21.3

Chromosomal abnormalities associated with psychiatric disorder. Entries in italics are negative findings. Column five (Criteria Met, CM) indicates if there is supportive evidence of an association through one or more of the following mechanisms: (IC) several Independent Cases of a rare chromosomal abnormality associated with a particular illness, (LK) co- localisation of the cytogenetic abnormality with a region of positive LinKage, or (CS) familial Co-Segregation of the cytogenetic abnormality with the condition. CS* indicates that the co-segregation reached statistical significance. Learning disability is the UK synonym for mental retardation.

Chromosome 15q t(14;18)(q11.2;q22.1) was reported.67 Two more in- Two interrelated patients with dysmorphisms and the dividuals, one with bipolar disorder and the other unbalanced derivatives of a reciprocal translocation with schizoaffective disorder, both with unbalanced t(15;18)(q13.3;q22.3), one with bipolar disorder and derivatives of a translocation t(15;18)(q13.3;q22.3), the other with schizoaffective disorder, were re- were described.57 In summary, chromosomal break- ported.57 Both had partial trisomy of chromosomes points at 18q21.1, 18q22.1 and 18q22.3 have been 15 and 18. Several schizophrenia linkage studies have reported. There has been linkage support for the given modest support to a susceptibility locus in the suggestion that susceptibility loci for bipolar dis- region 15q13–14,58–60 while others have failed to order68–70 and schizophrenia68 reside in the region of replicate those findings in separate populations.61,62 18q21–22. Although slightly proximal to the region of highest linkage, the association between Prader–Willi syn- drome at 15q11–13 and affective psychotic disorder Although the published literature in this area is and especially the recent striking finding of an limited, there is some evidence that individuals apparent excess of uniparental disomy cases is with trisomy 21 (Down’s syndrome) are at a decreased noteworthy.63 risk of developing bipolar disorder compared with In a study of families in which an interstitial other learning-disabled individuals or the general duplication, dup(15)(q24q26), cosegregated with population.71,27 This finding could be explained if a panic disorder, social phobia, agoraphobia and joint major susceptibility locus for bipolar disorder, a laxity, a Lod score of 5.0 was recorded. In an recessive disease allele, is present on chromosome extension of the original study the duplication was 21. A case report of a mother and daughter with found to be present in 97% of 70 unrelated panic chromosome 21p deletion and bipolar disorder72 disorder patients but only in 7% of a control group.24 adds some support to the suggestion that this locus might be on 21p. However, most linkage studies73–76 Chromosome 18p have indicated that if there is a locus for bipolar Cross-referencing Danish and Scottish cytogenetic disorder on chromosome 21, it lies in the region registers revealed two unrelated individuals with 21q21. the rare pericentric inversion, inv(18)(p11.3q21.1), one with schizophrenia and the other with bipolar Chromosome 22q disorder.64 There is supportive linkage to the 18p11 Initial interest was generated in this region when a region in bipolar disorder31,65 and in schizophrenia.66 paediatric craniofacial surgeon noticed high rates of psychiatric disorder, particularly schizophrenia, in Chromosome 18q patients with VCFS,77 a condition characterised by At a slightly terminal location to the breakpoint in distinctive dysmorphology, cardiac abnormalities and the two cases mentioned above, a woman with associated with small interstitial deletions of chromo- schizoaffective disorder and the translocation some 22q11.2. This deletion has an estimated

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 283 prevalence of 1 in 4000 live births, making it one As the volume of data generated by linkage studies of the most common genetic disorders. Further accumulates, several chromosomal loci that are likely studies have confirmed a high incidence of schizo- to be involved in schizophrenia, and several likely to phrenia and bipolar disorder78–80 in patients with be involved in bipolar disorder, are emerging. Chro- VCFS and a survey of 100 schizophrenic patients mosomal abnormalities have been reported in pa- discovered two with previously undiagnosed 22q11 tients with schizophrenia or bipolar disorder at many deletions.81 Several studies have reported linkage to of these sites. In two families, genes have already been markers near the VCFS region in schizophrenia,38,82 cloned that are directly disrupted by chromosomal and in that area and slightly telomeric to it in bipolar translocations. DISC1 and DISC2 are disrupted at disorder.84,85 1q42 in a large Scottish family segregating for schizophrenia and severe affective disorder. As Sex chromosome aneuploidy mentioned, there is linkage support for this locus There have been several studies published in the both within this family and from independent literature that found an excess of sex chromosome studies. In a separate study the gene DIBD1 coding in psychiatric patients. However, these for a mannosyltransferase enzyme has been found studies were either small or relied on the inaccurate disrupted by a translocation involving 11q23 in a 126 method of sex chromatin screening by buccal smear.28 family segregating for bipolar disorder. However A Japanese study that reported an excess of X there is, as yet, no further confirmation of its chromosome mosaicism in schizophrenic patients42 importance. Both these findings are recent and much was not replicated when an age-matched control work still has to be done to identify mutations in group was used.44 The only large-scale study so far other patients with illness. The most likely effect of cross-checked the Danish Cytogenetic and Psychiatric such direct gene disruption is gene silencing and thus Central Registers, and found no evidence of increased haploinsufficiency. This implies a dosage effect that risk for schizophrenia or bipolar disorder in people could be produced by a variety of direct or regulatory with sex chromosome aneuploidies.86 When schizo- dysfunctions in affected individuals without cytoge- phrenia and bipolar disorder were grouped together, netic rearrangements. Even if the genes were even- there was evidence, approaching statistical signifi- tually shown to be risk factors only in the families cance, of a decreased risk in those with Turner’s segregating for the chromosome abnormalities, they syndrome and an increased risk in men with the will generate new candidates through definition of 47,XYY karyotype. The latter finding is not easily interacting , for example, by the yeast-2- explainable. hybrid method. Another important study has reported an abnormality responsible for nonpsychotic panic Chromosome Xq disorder and agoraphobia. Provisional susceptibility A patient with bipolar disorder, learning disability loci for psychiatric disorders that have been identi- and an unusual translocation t(X;12)(q24;q15) was fied by chromosomal abnormalities are summarised reported.87 There have been several bipolar studies in Table 2. reporting linkage to markers in the Xq24–27 re- The reports reviewed in the present study support gion;88,89 however, these findings have not been the hypothesis that some genetic susceptibility f consistently replicated.13 actors are shared by schizophrenia and bipolar disorder: some families have a chromosomal abnorm- ality that cosegregates with both psychotic and Fragile sites affective disorder;15 some independent cases of rare There are reports of associations between schizo- abnormalities have been reported where one indivi- phrenia or bipolar disorder and numerous fragile dual has schizophrenia and the other has bipolar sites (see Table 1); however, none of these have disorder;64 and, lastly, patients with similar chromo- been consistently replicated. Furthermore, except somal deletions appear to have much increased rates at 1q32, linkage studies have not added support of schizophrenia and bipolar disorder.78 It would to the suggestion that any of these sites are therefore seem logical, in the first instance, to possible susceptibility loci. It is therefore possible concentrate the search for susceptibility loci on those that these fragile sites either represent artefacts areas that seem to be common to both conditions, or are coincidental findings of no clinical signifi- 90 using individuals with chromosomal aberrations to cance. help narrow the search. Furthermore, it would seem prudent to attempt to detect chromosomal aberrations Discussion in as many of those with psychiatric disorder as possible. It is unrealistic to expect cytogenetic That there are genetic components to psychiatric analysis to be performed on all psychiatric patients. disorders is not in question. Eventually, the chromo- However, there are several groups in whom screening somal regions harbouring the genes responsible will for cytogenetic abnormality should be seriously be identified and then the genes themselves will be considered, particularly those with (a) strong cloned. The questions are, which regions and how family histories of psychiatric disorder, (b) mild will the genes be identified? learning disability or a strong family history of

Molecular Psychiatry Chromosome abnormalities and mental illness DJ MacIntyre et al 284 Table 2 Susceptibility loci for psychiatric disorders identi- advance our search for the aetiology of psychiatric fied by chromosomal breakpoints illness.

Region Diagnosis (DSM-IV) Acknowledgements 1q42 SZ/BP/major depressive disorder 5q22–23 SZ DJ MacIntyre was a research registrar supported by 7q21 SZ the Wellcome Trust. WJ Muir, D Blackwood and DJ 9q34 SZ Porteous were in support of grant funding from the 10p12 SZ/BP 13q32 SZ/BP Scottish Executive, the Medical Research council. 15q13 BP/schizoaffective disorder The authors would also like to thank Dr Judy Fantes, 15q24 Panic disorder/agoraphobia/social phobia MRC Unit, Edinburgh for her helpful 18p11 SZ/BP comments on the manuscript. 18q21–22 BP 22q11–13 SZ/BP References SZ: schizophrenia; BP: bipolar disorder. For abnormalities co-segregating in families only those where the association 1 McGuffin P, Owen MJ, Farmer AE. Genetic basis of schizophre- was reported as statistically significant are listed. nia. Lancet 1995; 346: 678–682. 2 Craddock N, McGuffin P. Approaches to the genetics of affective disorders. Ann Med 1993; 25: 317–322. 3 Evans KL, Muir WJ, Blackwood DH, Porteous DJ. 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