Linkage Analysis between Manic-Depressive Illness and the Region on Chromosome 15q Involved in Prader-Syndrome, including Two GABA_A Receptor Subtype Genes

Abstract

Cooccurrence of Prader-Willi syndrome and psychosis has been reported in a few cases. Prader-Willi syndrome is most often associated with interstitial deletion or uniparental disomy of chromosome 15qll-ql3. The cooccurrence of Prader-Willi syndrome and psychosis may thus be due to deletion of, or in the case of uniparental disomy, duplication of a gene involved in the etiology of psychosis, possibly manic-depressive illness localized in this region. The region contains two assumed candidate genes for manic-depressive illness, the α₅ and β₃ sub-units of the γ-aminobutyric acid (GABA)_A receptor. This study investigates linkage between manic-depressive illness and this region. Furthermore, an additional case with Prader-Willi syndrome and psychosis is briefly described. No evidence of linkage was found assuming dominant or recessive modes of inheritance. Linkage to the GABA_A receptor subunits was excluded assuming a dominant mode of transmission for all models, and to the proximal part of the chromosome 15qll-ql3 region for broader phenotypic models. Negative though largely inconclusive lod scores were obtained assuming a recessive mode of transmission; however close linkage to the β₃ subtype of the GABA_A receptor was excluded.

Positive Association between the GABRA5 Gene and Unipolar Recurrent Major Depression

“…To date, linkage studies could not support a role for the GABRA5 gene in families with a bipolar proband [12][13][14], To our best knowledge no association studies on GABRA5 have been reported so far. In this study an asso ciation was found with allele 4 (282 base pairs) of a dinu cleotide repeat polymorphism located in the 3'-UTR of the GABRA5 gene in the overall patient sample (p = 0.017; table 1).…”

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium

“…[33][34][35][36][37][38][39] Most of these studies are reports of chromosomal aberrations in patients with bipolar disorder 34,36,[38][39][40] and one genome-wide study in a large Amish family that provided suggestive evidence with a marker on ch15. 35 Finally, positive linkage results were found between a gene that codes for ␣7-nicotinic receptor and sensory gating deficits in schizophrenic patients.…”

In search of the psychosis gene in people with Prader‐Willi syndrome

“…GABRB3 and GABRA5 subunit genes are also candidates for manic-depressive illness, although linkage studies have excluded the more proximal part of the (GABA)A receptor region, where the GABRB3 gene is located, as likely to harbor such a gene [Ewald et al, 1994]. Despite being handicapped by low expression levels, this study suggests that the GABAA receptor subunits are not involved in the development of psychotic episodes in people with PWS and suggests that it is dysregulation of a maternally inherited, paternally imprinted gene which is the cause.…”