J Hum Genet (2006) 51:1037–1045 DOI 10.1007/s10038-006-0058-5 MINIREVIEW Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia Tadao Arinami Received: 4 July 2006 / Accepted: 22 August 2006 / Published online: 13 September 2006 Ó The Japan Society of Human Genetics and Springer 2006 Abstract Schizophrenia is a severe, debilitating deletion region are conserved together on mouse mental disorder characterized by profound distur- chromosome 16, enabling the generation of mouse bances of cognition, emotion and social functioning. models. Similarities in the cardiovascular and other The lifetime morbid risk is surprisingly uniform at phenotypes between 22q11DS patients and mouse slightly less than 1% across different populations and models can provide important insights into roles of different cultures. The evidence of genetic risk factors genes in neurobehavioral phenotypes. Because more is our strongest clue to the cause of schizophrenia. than one gene in the 22q11DS region is likely to con- Linkage and association analyses have identified genes tribute to the marked risk for schizophrenia, further associated with the development of schizophrenia. extensive studies are necessary. Analyses of 22q11DS However, most of the alleles or haplotypes identified will help clarify the molecular pathogenesis of schizo- thus far have only a weak association or are reported to phrenia. be population specific. A deletion of 22q11.2 that causes the most common microdeletion syndrome Keywords Chromosome 22 Æ Microdeletion Æ (22q11DS) with an estimated prevalence of 1:2,500– Haploinsufficiency Æ Schizophrenia Æ 1:4,000 live births may represent one of the greatest Prepulse inhibition Æ Mouse model known genetic risk factors for schizophrenia. Schizo- phrenia is a late manifestation in approximately 30% of patients with 22q11.2 deletion, comparable to the Introduction risk to offspring of two parents with schizophrenia. Clinical and neuroimaging assessments indicate that Schizophrenia, a devastating mental disorder that af- 22q11DS-schizophrenia is a neurodevelopmental fects approximately 1% of the world’s population, is a model of schizophrenia. Recent studies have provided genetically complex disorder. The multifactorial poly- evidence that haploinsufficiency of TBX1 is likely to be genic model has received the most support for the responsible for many of the physical features associ- mode of inheritance responsible for the familial dis- ated with the deletion. Most of the genes in the 22q11 tribution of schizophrenia; therefore, a variety of ge- netic, environmental and stochastic factors are likely involved in the etiology. However, it is also possible T. Arinami (&) that specific genes play a major role in susceptibility to Department of Medical Genetics, schizophrenia, and efforts to identify such genes have Graduate School of Comprehensive Human Sciences, University of Tsukuba, revealed that an overall loss of DISC1 function by ei- Tsukuba, Ibaraki 305-8577, Japan ther haploinsufficiency or dominant-negative, or both e-mail: [email protected] (Ishizuka et al. 2006), or gene(s) involved in 22q11.2 deletion syndrome (22q11DS) substantially increases T. Arinami CREST, Japan Science and Technology Agency, susceptibility to schizophrenia. Alteration of DISC1 Kawaguchi-shi, Saitama 332-0012, Japan has been reported in only two families, whereas the 123 1038 J Hum Genet (2006) 51:1037–1045 22q11 deletion is detected relatively frequently in (borderline intellect, 51.3%; mild mental retardation, schizophrenia patients; a number of studies have 33.3% and moderate mental retardation, 7.7%). shown that 22q11DS-schizophrenia is a true genetic Adjusting for ascertainment source, 25.8% of patients subtype of schizophrenia (Bassett and Chow 1999; had cardiac anomalies and 22.6% had schizophrenia. Karayiorgou and Gogos 2004). Here I review recent studies of humans and rodents that have clarified the genetic basis for this specific subtype. Prevalence of the 22q11.2 deletion in unselected schizophrenia patients Several studies screened for 22q11.2 deletion in adult 22q11DS and psychiatric problems patients with schizophrenia. The first study found such a deletion in 2 of 100 patients with schizophrenia 22q11DS is the most common microdeletion syndrome, (Karayiorgou et al. 1995), and the second study found a with an estimated prevalence of 1:2,500–1:4,000 live deletion in 1 of 326 psychiatric inpatients (Sugama births (Tezenas Du Montcel et al. 1996; Oskarsdottir et al. 1999). The patient’s full IQ indicated mild et al. 2004). It is estimated that only 5–10% of 22q11.2 retardation with the verbal IQ being higher than the deletions are inherited (Scambler 2000). The deletion performance IQ. We screened 300 patients meeting the of 22q11.2 is associated with a wide variety of birth DSM-IIIR criteria for schizophrenia and identified 1 defects and malformations that occur in various com- patient with 22q11.2 deletion and mild retardation binations and with widely differing severity. 22q11DS (Arinami et al. 2001). Additional studies screened for is associated with several diagnostic labels including 22q11.2 deletion in a subset of schizophrenia patients. DiGeorge syndrome (DGS), velocardiofacial (or Usiskin et al. (1999) recruited 47 patients with child- Shprintzen) syndrome (VCFS), conotruncal anomaly hood onset schizophrenia and found that 3 carried a face, Cayler syndrome and Opitz GBBB syndrome. deletion of 22q11.2; all patients had premorbid 22q11DS is also associated with learning difficulties, impairment of language, motor and social develop- specific cognitive deficits and increased risk of neuro- ment. Thus, there is a 20- to 80-fold higher prevalence psychiatric disorders (Scambler et al. 1992; Swillen of the 22q11.2 microdeletion in patients with schizo- et al. 1997a, b; Henry et al. 2002). Attention-deficit/ phrenia relative to that of the general population. A hyperactivity disorder (ADHD) is one of the most deletion of chromosome 22q11.2 may represent one of common psychiatric problems associated with the greatest known genetic risk factors for schizo- 22q11DS in children. ADHD, primarily the inattentive phrenia. subtype, is present in 35–55% of 22q11DS cases (Gothelf et al. 2004a). In addition, approximately 11% of children with 22q11DS are autistic, and these chil- dren show greater developmental delay than those Psychopathologic characterization of 22q11.2 without autistic spectrum disorder (Fine et al. 2005). Other common psychiatric problems in children with Although many of physical symptoms in 22q11DS are 22q11DS include affective disorders such as bipolar well understood, far less is known about the apparent disorder and depression (Arnold et al. 2001). changes in brain structure and function, and their In adults with 22q11DS, high rates of obsessive- relation to the range of cognitive impairments and compulsive disorder (OCD) and schizophrenia have psychiatric disorders. A study of 33 children and adults been reported. In one study, diagnostic criteria for with 22q11DS reported a mean full-scale IQ in the OCD were fulfilled in 32.6% of individuals with borderline range of intellectural functioning 22q11DS (Gothelf et al. 2004b). Schizophrenia is a late (71.2±12.8) (Moss et al. 1999). With regard to psy- manifestation in approximately 30% of cases, which is chosocial and behavioral functioning, significantly ele- comparable to the risk to offspring of two parents with vated scores for the ‘‘social problems,’’ ‘‘attention schizophrenia. Bassett et al. (2005) described a study of problems’’ and ‘‘withdrawn’’ sub-scales were indicated 78 adults (age ‡17 years) with 22q11DS who met two by the Child Behvior Checklist (Swillen et al. 1997a, b). or more of seven broad categories of features (dys- Examination of the schizophrenia phenotype in morphic facies, hypernasal speech, history of learning individuals with 22q11DS without metal retardation difficulties, cardiac defect, thymic hypoplasia, other (IQ ‡70) revealed no significant differences in age at birth defects and hypocalcemia). Intellectual disability onset, lifetime or cross-sectional core positive and was observed in 92.3% of the adults with 22q11DS negative schizophrenic symptoms or global functioning 123 J Hum Genet (2006) 51:1037–1045 1039 between schizophrenic patients with 22q11DS and posterior brain regions may be indicative of corpus those without it. Thus, the core clinical schizophrenia callosum displacement due to enlarged cerebral ven- phenotype does not differ significantly between indi- tricles in individuals with 22q11DS. Campbell et al. viduals with the 22q11 deletion subtype and those with (2006) reported a significant reduction in cerebellar schizophrenia who do not have the 22q11 deletion grey matter and white matter reductions in the frontal subtype (Bassett et al. 2003). Because high rates of lobe, cerebellum and internal capsule in individuals congenital dysmorphic features, developmental struc- with 22q11DS. Among individuals with 22q11DS, a tural brain abnormalities and cognitive dysfunction in significant positive correlation was found between the 22q11DS are consistent with a subtype of schizophre- severity of the schizotypy score and grey matter vol- nia representing an especially neurodevelopmental ume of the temporo-occipital regions and the corpus form of the illness, the authors concluded that the striatum and between social behavioral difficulties and findings support the utility of 22qDS-schizophrenia as a grey matter volume in