MOLECULAR GENETICS OF BIPOLAR AFFECTIVE DISORDER

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The UCL Molecular Psychiatry laboratory has found evidence for linkage disequilibrium between multiple polymorphic genetic marker alleles and two affective disorder susceptibility loci on chromosome 12q23-24 and on chromosome 21q22. This means that the laboratory has fine mapped, or localised, two susceptibility genes for bipolar disorder to within a few hundred kilobases of genomic DNA at these loci for the first time. On chromosome 12q24 the region implicated contains seven genes with unknown functions. On chromosome 21q22 only two genes are implicated. The UCL lab. also has less well developed data for allelic association with two further affective disorder susceptibility loci which are at, or next to, the the Brain Derived Nerve Growth Factor (BDNF) gene on chromosome 11p13 and with a region at, or next to, the Glucose 6 Phosphate Dehydrogenase (G6PD) gene at Xq28. All four regions have previously been implicated by genetic linkage studies. We now wish to obtain support to produce a higher frequency SNP map across all four susceptibility loci which will include single nucleotide polymorphisms and possible aetiological mutations found by us from resequencing control regions and exons/splice sites/introns of the four candidate gene regions and from SNP databases. A fifth goal is to attempt to replicate all other reported allelic associations and putative aetiological DNA chnges found in bipolar disorder in the same UCL reference case/control sample of 625 bipolar cases and 625 supernormal controls. This will enable us to determine which loci are involved in a UK clinical sample and lead the way to understanding interaction between susceptibility loci and to determine the modes of genetic transmission for genetic subtypes of bipolar disorder. We also propose to study gene expression changes and regional brain distribution of the candidate genes we have already identified on chromosomes 12q24 and 21q22. If convincing aetiological mutations are found we will initiate transgenic and conditional mouse mutant studies, protein interaction studies and other neurochemical studies to determine the precise disease pathways. We will also initiate a programme of research relating genetic susceptibility markers and mutations to clinical variation in order to advance prevention, diagnosis, prognosis and treatment of affective disorders.