Alison Goate, Ph.D.
Professor of Genetics
Psychiatry
Professor
Genetics
Neurology
Human and Statistical Genetics
Molecular Genetics and Genomics
Neurosciences
314-362-8691
314-362-2573
314-747-1711
314-362-2244
8134
9th floor, BJC-IH
GOATE@WUSTL.EDU
http://hopecenter.wustl.edu/labs/goate/Pages/Overview.aspx
genetics, Alzheimer's disease, Alchohol dependence, nicotine dependence, dementia
Genetc and genomic approaches to uncover genetic susceptibility to neuropsychiatric disease
Research Abstract:
The principal focus of the laboratory is the molecular genetics of neuropsychiatric diseases. The two major research areas are Alzheimer's disease and substance dependence. We are using genetic (GWAS) and genomic (sequencing) strategies to identify rare and common alleles predisposing to these disorders. Our AD studies have recently focused on the use of cerebrospinal fluid biomarker levels such as A-beta and tau as quantitative traits in genetic analyses. These studies have demonstrated in humans that APOE influences risk for AD by an A-beta dependent mechanism. We have also demonstrated that two genes, which influence CSF tau levels, affect the rate of progression of AD but not risk for disease. GWAS using both of these phenotypes are ongoing and will complement our GWAS in case control datasets. A second project focused on rare variation has screened the proband from 450 densely affected late onset AD families for variation in the known dementia causing genes. This work has shown that at least 5% of these families have disease caused by mutations in genes previously associated with early onset disease. The largest families without pathogenic mutations will be used for whole exome sequencing for novel disease genes.
GWAS in nicotine dependence case control datasets has provided compelling evidence for the role of common risk variants in several nicotinic receptor sub-unit genes and in the major nicotine metabolism enzyme (CYP2A6). We are performing additional studies to determine the functional variants and the potential mechanism of risk. We have also undertaken sequencing studies to identify rare variation in the nicotinic receptor genes that might explain additional genetic variance. Our alcohol dependence study is a family based study. We are currently performing a GWAS in these families and have recently begun whole exome sequencing in a very large family with evidence for a single major locus influencing risk for alcohol dependence.
Selected Publications:
Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, Laurie C, Pugh E, Fisher S, Fox L, Howells W, Bertelsen S, Hinrichs AL, Almasy L, Breslau N, Culverhouse RC, Dick DM, Edenberg HJ, Foroud T, Grucza RA, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Krueger RF, Kuperman S, Lynskey M, Mann K, Neuman RJ, Nöthen MM, Nurnberger JI Jr, Porjesz B, Ridinger M, Saccone NL, Saccone SF, Schuckit MA, Tischfield JA, Wang JC, Rietschel M, Goate AM, Rice JP; Gene, Environment Association Studies Consortium. A genome-wide association study of alcohol dependence. Proc Natl Acad Sci U S A. 2010 107:5082-7.
Hinrichs AL, Mintun MA, Head D, Fagan AM, Holtzman DM, Morris JC, Goate AM. Cortical binding of pittsburgh compound B, an endophenotype for genetic studies of Alzheimer's disease. Biol Psychiatry. 2010 67:581-3.
Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 41:1088-93.
Wang JC, Cruchaga C, Saccone NL, et al. Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Hum Mol Genet. 2009 18:3125-35.
Kauwe JS, Cruchaga C, Mayo K, et al. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proc Natl Acad Sci U S A. 2008 105:8050-4.
Last Updated: 8/3/2011 4:13:51 PM