Linkage and association studies to uncover genetic susceptibility to neuropsychiatric disease.

The principal focus of the laboratory is the molecular genetics of neuropsychiatric diseases. The two major research areas are Alzheimer's disease and alcohol dependence, although smaller studies are underway on the genetics of other rare dementias and nicotine dependence. We are using genetic linkage and disequilibrium strategies to identify loci predisposing to these disorders. Our linkage studies in late onset AD have identified evidence for susceptibility loci on chromosomes 9, 10 and 12. The current focus of our AD genetics project is to identify the specific genes on these chromosomes. In addition to our search for novel genes we are also investigating the normal function and regulation of known AD genes including presenilin. We have recently demonstrated that a highly conserved PAL sequence in presenilins and presenilin homologues is essential for normal protease activity and likely part of the active site of these unusual proteases.

Linkage studies for alcoholism and related traits have identified evidence for susceptibility loci on chromosomes 4 and 7. Our current focus is the analysis of candidate genes on chromosome 7. Linkage disequilibrium analysis has demonstrated strong association between SNPs in the muscarinic acetylcholine receptor, M2 (CHRM2) and alcohol dependence. An overlapping set of SNPs also shows association with depression, providing evidence of pleiotropy. We are currently investigating the biological basis for the increased risk associated with hapotypes in the CHRM2 gene. Similar analyses have implicated a missense mutation in a bitter taste receptor as a risk factor for alcoholism.