Work carried out in the laboratory

Research in the MPL has used genetics as a method to understand the abnormal neurobiology causing schizophrenia, affective disorders and alcoholism. The MPL has completed genome wide linkage scans on family samples of schizophrenia, bipolar disorder and Tourette syndrome in order to localise susceptibility genes to specific regions of chromosomes. 

Genetic association studies with large case control samples were then used to fine map specific genes at the chromosomal linkage hot spots. The MPL showed that the CLINT1 (EPSIN 4), FXYD6, PCM1 and UHMK1(KIST) genes were implicated in genetic susceptibility to schizophrenia. The P2RX7 TRPM2 and another unknown gene on chromosome 12 were implicated in genetic susceptibility to bipolar disorder. 

Next, genome wide association scans with 500K or 1 million SNP arrays have been completed on schizophrenia and bipolar case control samples and are planned for the alcoholism case control sample, including sub samples of Wernicke Korsakov's syndrome and alcoholic cirrhosis of the liver. Some of the genes involved in affective disorders are also involved in susceptibility to alcoholism. 

Families of glutamate receptor genes as well as calcium channel genes have now been implicated in schizophrenia as well as bipolar disorder. A second major effort in the MPL concerns the use of systems biology and pharmacogenomics to point the way to new drug and preventive strategies for the psychoses. Initially gene expression studies of antipsychotic drugs were carried out to identify glutamatergic receptor changes. Later, microarray studies of lithium, clozapine and haloperidol were carried out. This was followed by pathways analysis. 

More recently genetic association data on bipolar disorders and schizophrenia has been converged with gene expression data on lithium, clozapine and haloperidol. The laboratory has established large case control samples in which known aetiological base pair changes have been implicated and it has been possible to correlate clinical changes at the level of brain morphology with genetic effects from the PCM1 gene on chromosome 8. 

The MPL has also been collaborating with research groups at UCL and Imperial College who have established convincing animal models for ADHD and alcoholism. This has led to the finding of two human genes which are increasing susceptibility to alcoholism and ADHD.