Schizophrenia 1

For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.

Mapping

Sklar et al. (2004) reported linkage to an overlapping region at chromosome 5q31.1-q35.1 in a genomewide scan of schizophrenia and schizoaffective disorder depressed subtype families of Portuguese descent. The maximum linkage signal in 29 families was an NPL = 3.09 (p = 0.0012) at marker D5S820, falling just short of genomewide significance based on simulations of the data. Higher density mapping in an expanded sample of 40 pedigrees produced a peak NPL = 3.28 (p = 0.00066) in the same region. Nominally significant linkage was obtained across a 35 cM region from D5S816 to D5S1456. A metaanalysis of 20 schizophrenia genomewide scans by Lewis et al. (2003) supported these findings by identifying 5q23.2-q34 as the second most compelling schizophrenia susceptibility locus in the genome.

Pimm et al. (2005) studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Testing adjacent markers at the 5-prime end of the epsin-4 gene (EPN4; 607265), they found significant evidence of linkage disequilibrium with schizophrenia. The variation included 2 microsatellite markers and 2 SNPs within the EPN4 gene. A series of different 2- and 3-marker haplotypes were significantly associated with schizophrenia. The epsin-4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. Pimm et al. (2005) suggested that a genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.

Petryshen et al. (2005) conducted a 2-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes located at 5q31-q35, within the linkage peak identified by Lewis et al. (2003). These genes were studied because of prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with SNPs and haplotypes in GABRA1 (137160) (p = 0.00062-0.048), GABRP (602769) (p = 0.0024-0.042), and GABRA6 (137143) (p = 0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (p = 0.0015-0.043). Analysis of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2 (600232). Comparison of transcript levels in schizophrenia patients and unaffected sibs found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Petryshen et al. (2005) interpreted these results support the involvement of the chromosome 5q GABA-A receptor gene cluster in schizophrenia.

Sherrington et al. (1988) studied 5 Icelandic and 2 English families, with 39 cases of schizophrenia (including all the main subtypes, such as paranoid and hebephrenic), 5 cases of related schizoid personality disorder, and 10 cases of 'fringe' phenotypes not usually associated with schizophrenia (such as phobic disorder, anxiety disorder, and major depressive disorder). They found a maximum lod score of 6.49 at 86% penetrance in an analysis that assumed dominant inheritance and included schizophrenia, schizophrenia spectrum disorders, and all other fringe phenotypes. In a study of a single, well-documented kindred in a geographic isolate located above the Arctic circle (described by Book, 1953, and Book et al., 1978), Kennedy et al. (1988) found no evidence of linkage to chromosome 5 markers. As pointed out by Lander (1988), the findings are consistent with the existence of 2 genetic types of schizophrenia. He also pointed out that a unique form of schizophrenia may be present in the Icelandic families, whereas another form may exist in the northern Swedish families.

In studies of 15 Scottish families with schizophrenia, St. Clair et al. (1989) found no evidence of linkage to 5q11-q13 markers. A similar conclusion was arrived at by Detera-Wadleigh et al. (1989) in a study of North American pedigrees. In 7 North American families with schizophrenia, Aschauer et al. (1990) could find no evidence for linkage to markers spanning the region 5p13-q14. In 6 Welsh families with multiple cases of schizophrenia, McGuffin et al. (1990) could find no evidence of linkage between a schizophrenia gene and 5q11-q13 markers. They argued that these results, combined with a reanalysis of previous studies, suggest that a schizophrenia susceptibility locus (SSL) can be excluded from that region. They interpreted the disparity of earlier studies as indicating a chance finding in one positive study and not an indication of true linkage heterogeneity. King et al. (1997) likewise excluded linkage of schizophrenia to the short arm of chromosome 5. They were prompted to undertake this study because the human dopamine transporter gene (126455) is located at 5p15.3 and genetic linkage to a closely situated marker had been reported by Silverman et al. (1996).

Paunio et al. (2001) conducted a genomewide scan in a nationwide Finnish schizophrenia study sample of 238 pedigrees with 591 affected individuals. Of the 238 pedigrees, 53 originated from a small internal isolate on the eastern border of Finland. In addition to the previously identified chromosome 1 locus, 2 new loci were identified in the cohort on chromosomes 2q and 5q. The highest lod scores were found in the internal isolate families with marker D2S427 (Zmax = 4.43) and in the families originating from the late settlement region with marker D5S414 (Zmax = 3.56).

Cytogenetics

The existence of a locus on the long arm of chromosome 5 that contributes to the etiology of schizophrenia was suggested by Bassett et al. (1988), who described 2 members of a family from Vancouver, an uncle and nephew, both of whom were schizophrenic at an early age and were partially trisomic for chromosome 5q11.2-q13.3. Both men were mildly dysmorphic with frontal bossing, flat occiput, hypertelorism, protuberant ears, short stature, short fourth proximal phalanx of the toes bilaterally, partial syndactyly of the fingers and toes, renal abnormalities on ultrasound, and small phallus. Neither individual had neurologic dysfunction or mental retardation. The woman who was mother and sister of the affected men was phenotypically normal; her chromosomes showed a balanced translocation t(1;5)(q32.3;q13.3q11.2). All other available members of the family had normal chromosomes and normal phenotype without schizophrenia, although the parents of the uncle were deceased and hence unavailable for study. One man had unilateral absence of the kidney, and the other had partially duplicated and inferiorly displaced kidney (Wood et al., 1988), anomalies consistent with hereditary renal adysplasia (HRA; 191830); thus the locus for HRA may lie within this region. Wood et al. (1988) reported a dosage study of this Vancouver family showing that the derivative chromosome 1 was carrying a RFLP allele at the HEXB locus (606873), which is known to be located in band 5q13. McGillivray et al. (1990) showed that the HEXB locus was present in 3 copies in both affected males and gave a full report of the clinical features in this informative family. Following the lead provided by the Vancouver family, 2 groups did linkage studies using DNA markers from 5q, including the gene for glucocorticoid receptor (GRL; 138040), which is a possible candidate for a schizophrenia-susceptibility gene because perturbations in glucocorticoid metabolism can induce psychotic symptoms.

Malaspina et al. (1992) reported a girl with a partial trisomy of 5p which was cytologically distinct from that reported by Bassett et al. (1988). She had low normal intelligence and a few minor physical anomalies, and was diagnosed with schizophrenia at age 8 years. Her father, who was well except for a generalized anxiety disorder, was a carrier of a balanced (5;14)(p14.1;q32.3) translocation, as was a phenotypically normal brother. A brother with the same partial 5p trisomy had refractory epilepsy, whereas another brother had a partial 5p monosomy and the cri du chat syndrome.