Dr. Qing-Rong Liu obtained his bachelor degree in Biochemistry and master degree in Genetics at Peking University. He earned his Ph.D. at Baylor College of Medicine majoring in Pharmacology and Molecular Biology in 1991. He worked as research scientist in Pharmaceutical Companies of Hoffmann-la Roche and Hoechst-Roussel and discovered several novel drug targets such as GABA, Glycine, and Taurine neurotransmitter transporters. His strong interest in Psychiatric Genetics leads him to genome wide association study (GWAS) on addiction vulnerable genes using Affymetrix chips of high density single nucleotide polymorphism (SNP) and copy number variants (CNV). He has identified brain derived neurotrophic factor (BDNF) and several cell adhesion molecules (CAM) as susceptible genes for drug abusers. He is currently working as staff scientist at National Institute on Drug Abuse and his research involves combination of bioinformatics and experimental approaches to identify genetic predisposition markers for complex diseases and underlying molecular mechanisms.

Tentative Title

Genome wide association study (GWAS) and molecular biology approach to identify cell adhesion molecules (CAM) as susceptibility genes for addiction

Abstract

Vulnerability to drug abuse is a complex trait with strong genetic influences. Using Affymetrix 500K and 1M microarrays to scan DNA samples from two samples of polysubstance abusers vs two samples of ethnically-matched controls, 13 cell adhesion molecule (CAM) genes were identified within SNP clusters that significantly associated with drug abusers in both scans. These CAMs are expressed in neurons linked to reward and memory. CAMs are usually single tramsmembrane protein containing multiple extracellular domains such as immunoglobulin, fibronectin, cub-sushi, cadherin, laminin and intracellular PDZ domains. Neurexins are cell adhesion molecules that help to specify and stabilize synapses and provide receptors for neuroligins, neurexophilins, dystroglycans and ¦Á-latrotoxins. Fine mapping localized the association signal to the vicinity of the NRXN3 splicing site 5 (SS#5). A splicing site SNP, rs8019381, that is located 23 bp from the SS#5 exon 23 donor site displays association with p = 0.0007 (odds ratio = 2.46) to alcoholism. Including or excluding exon 23 at SS#5 produces soluble or transmembrane NRXN3 isoforms. We thus examined expression of these NRXN3 isoforms in postmortem human cerebral cortical brain samples from individuals with varying rs8019381 genotypes. Two of the splice variants that encode transmembrane NRXN3 isoforms were expressed at significantly lower levels in individuals with the addiction-associated rs8019381 ¡°T¡± allele than in CC homozygotes. These data support roles for NRXN3 haplotypes that alter expression of specific NRXN3 isoforms in genetic vulnerabilities to dependence on a variety of addictive substances. However, despite increasing recognition of functional and pathological significance of CAMs, no systematic study has enumerated CAMs or documented their global features. We have mapped CAM genes onto novel cell adhesion molecule ontology (CAMO) that provides a hierarchical description of cell adhesion molecules and their functions. We have identified global properties of these CAM genes that contains 850 terms and up to seven levels of data, including gene regulation, relationships to human Mendelian and complex diseases, copy number variants, recombination hot spots, alternative splicing, and sites for microRNA regulation.