Alternative titles; symbols
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:148,000,001-156,040,895
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | {?Major affective disorder 2} | 309200 | X-linked dominant | 2 |
The notion of an X-linked form of manic-depressive illness dates back to at least the 1930s when an excess of affected females and a deficiency of male-to-male transmission made this an attractive possibility. The paper by Reich et al. (1969), reporting linkage to colorblindness (see 303800) in 2 kindreds, was a landmark among reports of genetic studies of mental illness. Winokur and Tanna (1969) suggested X-linked dominant inheritance. Without reference to specific genetic hypothesis, Mendlewicz et al. (1972) reported that bipolar (manic-depressive) patients with a family history of similar illness responded better to lithium than those without affected relatives. Mendlewicz and Rainer (1974) concluded further that their data were consistent with X-linked dominant inheritance of manic-depressive illness, with linkage to colorblindness and to Xg loci. Since the latter two loci are far apart, indeed on different arms of the X chromosome, that conclusion on linkage is suspect. Bipolar and unipolar illnesses are distinct. In the bipolar condition, mania occurs sometime during the course of the affective illness. In the unipolar condition, only depressive episodes occur. The evidence for distinctness consists of (a) clinical data which show differences in length and number of episodes and age of onset, and (b) familial data which show high rate of psychosis, especially mania, in bipolar families. It is the bipolar families in which X-linked dominant inheritance has been suggested. Cadoret and Winokur (1975) reviewed the evidence. Mendlewicz et al. (1980) studied a large family of Persian Sephardic Jewish origin in which both manic-depressive psychosis and G6PD deficiency (300908) were segregating. A lod score of 4.32 was obtained for a recombination fraction slightly less than 0.05. (Autosomally transmitted genetic susceptibility has also been demonstrated; see 125480.) Risch et al. (1986) reanalyzed 2 bodies of data, one from a family study of bipolar affective illness in New York (Mendlewicz and Rainer, 1974) and the other from a similar study in Bethesda (Gershon et al., 1982). They concluded that X-linkage exists, but that only a subgroup, possibly one-third, of 'bipolars' carry the X-linked gene. The X-linked subgroup may be associated with early onset (before 30 years of age). As they indicated, linkage studies with X-chromosome RFLP markers will be of great interest and possible usefulness. Baron et al. (1987) studied a new series of pedigrees and again found linkage of bipolar affective illness with colorblindness and G6PD (305900). The maximum lod score ranged from 7.52 (assuming homogeneity) to 9.17 (assuming heterogeneity). The probands originated from the patient population of the Jerusalem Mental Health Center. One pedigree was Polish-Ashkenazi and 4 were non-Ashkenazi originating from Iraq, Yemen, Turkey, and Iran. The Ashkenazi pedigree gave negative lod scores.
Mendlewicz et al. (1987) found a maximum lod score of 3.10 at a recombination fraction of 0.11 for linkage between a manic-depressive locus and the factor IX locus at Xq27 as defined with a TaqI polymorphism. In studies of 7 informative kindreds segregating for manic-depressive illness in a pattern consistent with X-linked inheritance (no instance of father-to-son transmission), Gejman et al. (1990) found lod scores consistently less than -2 in a segment extending from about 10 cM centromeric to F9 to the region of the colorblindness genes.
Hebebrand (1992) pointed out that formal genetic evidence for X-linked dominant inheritance is lacking. There appeared to be two main reasons for this: (1) segregation ratios among the offspring of affected males could not be evaluated adequately because most males had either not reproduced or their offspring were not considered informative by the investigators; and (2) the assumed hemizygous males had not been shown to be more severely affected than the heterozygous females. Hebebrand and Hennighausen (1992) quantitatively evaluated specific segregation patterns and clinical data in 8 positive X-linkage studies including those of Mendlewicz et al. (1972, 1980, 1987) and Baron et al. (1987). They suspected that the pedigree structures observed resulted from ascertaining kindreds with autosomal or multifactorial inheritance, with exclusion of kindreds encompassing male-to-male transmission.
Baron et al. (1993) extended and reevaluated pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, in 3 multigeneration Israeli kindreds. The results showed greatly diminished support for linkage to Xq28. The peak lod scores in 2 of the pedigrees had dropped several lod units to values clearly negative at the RCP--F8--G6PD gene cluster. On the other hand, positive lod scores (maximum = 2.09) at the same map location were sustained in another pedigree. None of the pedigrees showed linkage to more proximal markers, including the Xq28 locus DXS98. Pauls (1993) commented on the problems of linkage analysis in behavioral disorders and outlined methodologic strategies that probably will be necessary for success of molecular genetic studies. Both Baron et al. (1994) and Gershon and Goldin (1994) emphasized that despite the suggestion by Bocchetta et al. (1994) of linkage of bipolar disorder to Xq28, there is no consistent statistical evidence of linkage.
Thomson et al. (2005) investigated the GPR50 gene (300207) as a candidate for mutation in bipolar affective disorder. They compared the allele frequencies of 3 GPR50 polymorphisms in case-control studies of 264 individuals with BPAD, 226 with major depressive disorder (MDD; see 608516), 263 with schizophrenia (see 181500), and 562 ethnically matched controls. A significant association was found between an insertion/deletion polymorphism (del502-505) in exon 2 and an increased risk of both BPAD (p = 0.0070) and MDD (p = 0.011). Analysis restricted to females showed an increase in the association with BPAD and MDD (p = 0.00023 and p = 0.0064, respectively). One SNP (rs13440581) showed weak association with MDD in females (p = 0.0096), and another (rs2072621) showed significant association with schizophrenia in females (p = 0.0014). Thomson et al. (2005) suggested that the deletion variant, or a variant in linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to BPAD and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia.
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