Mental Disorders; Genetics; 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.
- Xiang Y, Kim K-Y, Gelernter J, Park I-H, Zhang H*. Ethanol upregulates NMDA receptor subunit gene expression in human embryonic stem cell-derived cortical neurons. PLoS ONE 2015; 10(8): e0134907.
- 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; 133(11):1383-94.
- 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; 133(9):1093-1104.
- 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; 23(5):1260-70.
- 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; 4(155). pii: 18179.
- Zhong L and Zhang H*. Analyzing Interaction of mu-, delta- and kappa-opioid Receptor Gene Variants on Alcohol or Drug Dependence Using a Pattern Discovery-based Method. J Addict Res Ther. 2013; S7: 007.
- 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; 8(6): e65648.
- Wang F, Simen A, Arias AA, Zhang H*. A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum Genet. 2013; 132(3):347-58.
- 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; 37 Suppl 1:E101-7.
- 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; 37 Suppl 1:E108-15.
- Wang F, Gelernter J, Kranzer HR, Zhang H*. Identification of POMC Exonic Variants Associated with Substance Dependence and Body Mass Index. PLoS One. 2012; 7(9): e45300.
- 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; 57(10):670-5.
- 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; 8:23.
- 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; 35(11):2211-24.
- 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; 55(5):278-84.
- 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; 42(1):85-92.
- Zhang H*, Kranzler HR, Poling J, Gruen JR, Gelernter J. Cognitive flexibility is associated with KIBRA variant and modulated by recent tobacco use. Neuropsychopharmacology. 2009; 34(12):2508-16.
- Zhang H*, Kranzler HR, Weiss RD, Luo X, Brady KT, Anton RF, Farrer LA, Gelernter J. Pro-opiomelanocortin gene variation related to alcohol or drug dependence: evidence and replications across family- and population-based studies. Biol Psychiatry. 2009; 66(2):128-36.
- Zhang H*, Kranzler HR, Yang BZ, Luo X, Gelernter J. The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Mol Psychiatry. 2008; 13(5):531-43.
- Zhang H*, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, Zvartau E, Gelernter J. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet. 2006; 15(6):807-19.
- 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; 141B(4):387-93.
- 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.