This first revision of a K08 proposal requests support to provide Falk W. Lohoff, MD, with a five-year period of supervised research training that will enable him to become a successful independent investigator in human psychiatric genetics, utilizing translational and functional genomics research approaches. Project Summary: This is an application to investigate the vesicular monoamine transporter 1 gene (VMAJ1/SLC18A1) as a candidate gene for bipolar disorder (BPD) and schizophrenia (SZ). The SLC18A1 gene maps to chromosome 8p, a region with confirmed linkage for BPD and SZ. Multiple linkage peaks in this region and inconsistent results of previous candidate gene studies (i.e. neuregulin 1), suggest genetic heterogeneity and the existence of additional susceptibility genes in the 8p21 region. We hypothesize that the vesicular monoamine transporter 1 (VMAT1/SLC18A1) gene is an 8p21 susceptibility gene for both SZ and BPD. Preliminary data show that the VMAT1 gene is associated with BPD and SZ. In addition, we have generated evidence of VMAT1 brain expression and identified novel splice variants. VMAT1 brain expression is a novel finding and could change fundamentally our perspective of monoamine neurotransmission.
Specific Aims of Research Plan: 1) Sequencing: Sequencing of SLC18A1 exons and regulatory regions (promoter, 3'UTR) in 100 BPD and 100 SZ samples from the NIMH Genetics Initiative will be carried out. This will allow detection of uncommon variants associated with disease. 2) Genotyping and association analyses: Common variants will be genotyped in -2000 BPD, -2500 SZ and -2000 control DMA samples from the NIMH Genetics Initiative. 3) Functional analysis of variants: Alleles (haplotypes) of SLC18A1 which are associated with either BPD or SZ and novel identified splice variants will be expressed and translated in cell lines. Rates of transcription, translation and protein function (Vmax and Km) will be assessed for the wild-type, disease-associated variants and splice variants. Training Plan: Training in research methods in human genetics, bioinformatics and statistical genetics and functional analyses using in vitro methods is important for the candidate's career development and is necessary for his future research independence. The training will be conducted at the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania. The candidate will take relevant courses and will attend research meetings. Dr. Wade Berrettini will be the mentor, and Drs. Irwin Lucki, Cameron Gundersen, Steven Arnold, Thomas Ferraro and Mingyao Li will provide additional consultation. Relevance: BPD and SZ are chronic disabling psychiatric disorders with strong genetic components to their etiologies. Identifying genetic risk factors will lead to better diagnosis and improved treatment of the disorders. ? ? ?
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