Mental Disorders; Genetics; Psychiatry; Stem Cells; Genomics; Epigenomics
We are examining genetic and epigenetic changes that may increase the risk for substance dependence and related psychiatric disorders.
Specialized Terms: Substance Dependence; Psychiatric Genetics; Epigenetics; Functional genomics; Stem cell
Extensive Research Description
Our research goal is to understand the genetic and epigenetic mechanisms of substance (alcohol or drug) dependence and related psychiatric disorders. We are using a number of approaches [such as candidate gene and genome-wide association studies (GWAS) as well as next-generation sequencing (NGS) technologies] to identify gene variants that influence the vulnerability to the disorders. We are also profiling transcriptomic and epigenomic changes (such as mRNA and microRNA as well as DNA methylomic alterations) in saliva, blood, and reward-related brain regions of subjects affected with substance dependence. Transcriptomic and epigenomic changes identified in postmortem brains of human subjects affected with substance dependence are being validated using a mouse model. Moreover, we are performing post-GWAS research to (1) prioritize substance dependence-associated variants using bioinformatics approaches, and (2) study the function of prioritized variants (particularly noncoding variants) using massive parallel reporter assay and RNA sequencing (MPRA/RNA-Seq). Additionally, we are using human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived neurons as models to study the molecular and cellular mechanisms of substance dependence.
- Zhang H*, Liu X, Zhang C, Mundo E, Macciardi F, Grayson DR, Guidotti AR, Holden JJ. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry. 2002;7(9):1012-7.
- Zhang H*, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, Price LH, Southwick S, Yang BZ, Rasmussen A, Gelernter J. Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet. 2006 Jun 5;141B(4):387-93
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- Zhang H*, Wang F, Kranzler HR, Anton RF, Gelernter J. Variation in regulator of G‐protein signaling 17 gene (RGS17) is associated with multiple substance dependence diagnoses. Behav Brain Funct. 2012 May 16;8:23.
- Zhang H*, Herman AI, Kranzler HR, Anton RF, Simen AA, Gelernter J. Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence. J Hum Genet. 2012 Oct;57(10):670‐5.
- Wang F, Gelernter J, Kranzler HR, Zhang H*. Identification of POMC exonic variants associated with substance dependence and body mass index. PLoS One. 2012;7(9):e45300.
- Zhang H*, Smith GN, Liu X, Holden JJ. Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas. Physiol Genomics. 2010 Jun;42(1):85-92.
- Zhang H*, Gelernter J, Gruen JR, Kranzler HR, Herman AI, Simen AA. Functional impact of a single‐nucleotide polymorphism in the OPRD1 promoter region. J Hum Genet. 2010 May;55(5):278‐84.
- Zhang H*, Herman AI, Kranzler HR, Anton RF, Zhao H, Zheng W, Gelernter J. Array‐based profiling of DNA methylation changes associated with alcohol dependence. Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1:E108‐15.
- Barker JM, Zhang Y, Wang F, Taylor JR, Zhang H*. Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1:E101-7.
- Zhang H*, Kranzler HR, Poling J, Gelernter J. Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5‐CHRNA3‐CHRNB4 and its interaction with recent tobacco use influence cognitive flexibility. Neuropsychopharmacology. 2010 Oct;35(11):2211‐24.
- Wang F, Simen A, Arias A, Lu QW, Zhang H*. A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum Genet. 2013 Mar;132(3):347-58.
- Zhang H*, Wang F, Kranzler HR, Zhao H, Gelernter J. Profiling of childhood adversity‐associated DNA methylation changes in alcoholic patients and healthy controls. PLoS One. 2013 Jun 14;8(6):e65648.
- Li Z, Zhang H*. Analyzing Interaction of μ-, δ- and κ-opioid Receptor Gene Variants on Alcohol or Drug Dependence Using a Pattern Discovery-based Method. J Addict Res Ther. 2013 May 14;Suppl 7:007.
- Wang F, Gelernter J, Zhang H*. Differential Expression of miR‐130a in Postmortem Prefrontal Cortex of Subjects with Alcohol Use Disorders. J Addict Res Ther. 2013 Jul 23;4(155). pii: 18179.
- Xu H, Wang F, Liu Y, Yu Y, Gelernter J, Zhang H*. Sex‐biased methylome and transcriptome in human prefrontal cortex. Hum Mol Genet. 2014 Mar 1;23(5):1260‐70.
- Zhang H*, Wang F, Kranzler HR, Yang C, Xu H, Wang Z, Zhao H, Gelernter J. Identification of methylation quantitative trait loci (mQTLs) influencing promoter DNA methylation of alcohol dependence risk genes. Hum Genet. 2014 Sep;133(9):1093‐104.
- Zhang H*, Wang F, Xu H, Liu Y, Liu J, Zhao H, Gelernter J. Differentially co‐expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: influence on alcohol metabolism‐related pathways. Hum Genet. 2014 Nov;133(11):1383‐94.
- Xiang Y, Kim KY, Gelernter J, Park IH, Zhang H*. Ethanol upregulates NMDA receptor subunit gene expression in human embryonic stem cell‐derived cortical neurons. PLoS One. 2015 Aug 12;10(8):e0134907.
- Wang F, Xu H, Zhao H, Gelernter J, Zhang H*. DNA co‐methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. Scientific Reports. 2016 Jan 14;6:19430.
- Zhang H*, Gelernter J. DNA methylation and alcohol use disorders: Progress and challenges. Am J Addict. 2016 Oct 19.
- Xu H, Wang F, Kranzler HR, Gelernter J, Zhang H*. Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes. Scientific Reports. 2017. In Press.