A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

Abstract

There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity ( 2 = 18.8, df = 2, P = 0.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC) n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

“…4p16, 8p22, 10p14, 13q32, 18p11 and 22q11-13. [4][5][6][7] Several studies have suggested linkage of especially SZ but also BPD to a number of regions on chromosome 22. 8 This has been supported by meta-analyses.…”

Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus

“…4,5 However, problems with incomplete penetrance, locus heterogeneity and an insufficient number of reliable meioses likely account for the inability to replicate and extend the results. Recent large-scale genetic linkage studies of bipolar disorder using non-parametric, allele-sharing methods have identified several interesting chromosomal regions including 4p16, 6,7 12q23-24, [8][9][10][11] 21q22, [12][13][14][15] 18q21, 16,17 18q22 18,19 and the centromere of 18. 20 Although it is premature to draw any conclusions about these reported linkages until gene(s) for bipolar disorder are identified, several general observations can be made: no finding replicates in all data sets, the effect sizes are small, statistical significance has not reached genome-wide levels, and the regions identified are large (generally Ͼ20 cM) and difficult to approach by positional cloning.…”

Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands

“…11 Linkage between D4S394 (4p16.1) and bipolar affective disorder was initially reported by Blackwood et al 4 Other surveys have provided additional evidence for linkage of bipolar affective disorder or schizophrenia to markers in this region and other regions on chromosome 4. [5][6][7][8][9] There are, however, also negative reports of linkage of bipolar affective disorder or schizophrenia to chromosome 4. 9,[19][20][21] When considering bipolar patients, two segments (D4S394-D4S2983 and D4S2923-D4S2928-D4S1582) at 4p16.1 received some support (Table 1).…”

“…1,2 The two disorders may share genetic and nongenetic risk factors. 3 Significant linkage of markers to 4p16 has been found in several families segregating for bipolar disorder or schizophrenia, [4][5][6][7][8][9] which makes this a candidate region for susceptibility gene(s). Perhaps the most interesting candidate gene in this region is the gene coding for the dopamine type 5 receptor (DRD5), 10 as malfunction of the dopamine system has been implicated in psychotic disorders.…”