Research Areas

Broadly, our research centers around human heredity and the somatic cell biology of mutations that produce disease. Our interests encompass psychiatric genetics, addiction biology and mechanisms of gene regulation and include the production of induced pluripotent stem cell (iPSC) and engineered mouse genetic models for disease as key tools to understand biological mechanisms.

Research Highlights

One research focus is Tourette disorder (TD), a neuropsychiatric condition that is characterized by verbal and motor tics and which is observed in about 1 in 150 children. We have analyzed inherited, disease-producing genetic variants of specific genes in large TD families using neurons derived from iPSCs and molecular genetics tools. In contrast, our “TIC Genetics” collaborative group has discovered and is now characterizing new gene mutations that have arisen in the TD children of unaffected parents. We aim to understand how these gene variants function on a cellular level by comparing iPSC-derived neurons from affected and unaffected individuals. At the same time, we hope to model TD behavior, neuroanatomy and neurophysiology with mice engineered to have mutations identical to those that we have discovered in TD humans.

Other research foci include collaborative research on the genetics and functional mechanisms of alcohol abuse and cellular opioid responses. We also continue with loss of heterozygosity (LOH) experiments to determine what features along the mitotic chromosome promote recombination that results in LOH. Additional lab projects include development of drugs to treat cystinuria, a disease characterized by painful, recurrent cystine kidney stones, using an engineered mouse model for cystinuria.

Recent Publications

Cross-Disorder Group of the Psychiatric Genomics Consortium. Electronic address:  lee0@mgh.harvard.edu; Cross-Disorder Group of the Psychiatric Genomics Consortium. (606 Collaborators.) Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell. 2019 Dec 12;179(7):1469-1482.e11. doi: 10.1016/j.cell.2019.11.020.

Salvatore JE, Barr PB, Stephenson M, Aliev F, Kuo SI, Su J, Agrawal A, Almasy L, Bierut L, Bucholz K, Chan G, Edenberg HJ, Johnson EC, McCutcheon VV, Meyers JL, Schuckit M, Tischfield J, Wetherill L, Dick DM.  Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis. Addiction. 2019 Oct 28. doi: 10.1111/add.14815. [Epub ahead of print]

Meyers JL, Chorlian DB, Johnson EC, Pandey AK, Kamarajan C, Salvatore JE, Aliev F, Subbie-Saenz de Viteri S, Zhang J, Chao M, Kapoor M, Hesselbrock V, Kramer J, Kuperman S, Nurnberger J, Tischfield J, Goate A, Foroud T, Dick DM, Edenberg HJ, Agrawal A, Porjesz B.  Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood.  Brain Sci. 2019 Oct 17;9(10). pii: E280. doi: 10.3390/brainsci9100280.

Halikere A, Popova D, Scarnati MS, Hamod A, Swerdel MR, Moore JC, Tischfield JA, Hart RP, Pang ZP. Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons.  Mol Psychiatry. 2019 Sep 3. doi: 10.1038/s41380-019-0507-0. [Epub ahead of print]

Rao X, Thapa KS, Chen AB, Lin H, Gao H, Reiter JL, Hargreaves KA, Ipe J, Lai D, Xuei X, Wang Y, Gu H, Kapoor M, Farris SP, Tischfield J, Foroud T, Goate AM, Skaar TC, Mayfield RD, Edenberg HJ, Liu Y.  Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.  Mol Psychiatry. 2019 Sep 2. doi: 10.1038/s41380-019-0508-z. [Epub ahead of print]

Lai D, Wetherill L, Kapoor M, Johnson EC, Schwandt M, Ramchandani VA, Goldman D, Joslyn G, Rao X, Liu Y, Farris S, Mayfield RD, Dick D, Hesselbrock V, Kramer J, McCutcheon VV, Nurnberger J, Tischfield J, Goate A, Edenberg HJ, Porjesz B, Agrawal A, Foroud T, Schuckit M.  Genome-wide association studies of the self-rating of effects of ethanol (SRE).  Addict Biol. 2019 Jul 3:e12800. doi: 10.1111/adb.12800. [Epub ahead of print]

Vazquez BN, Thackray JK, Simonet NG, Chahar S, Kane-Goldsmith N, Newkirk SJ, Lee S, Xing J, Verzi MP, An W, Vaquero A, Tischfield JA, Serrano L.  SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina.  Nucleic Acids Res. 2019 Sep 5;47(15):7870-7885. doi: 10.1093/nar/gkz519. PMCID: PMC6735864.

Woodard LE, Welch RC, Veach RA, Beckermann TM, Sha F, Weinman EJ, Ikizler TA, Tischfield JA, Sahota A, Wilson MH.  Metabolic consequences of cystinuria.  BMC Nephrol. 2019 Jun 20;20(1):227. doi: 10.1186/s12882-019-1417-8.  PMCID:  PMC6585015

Wetherill L, Lai D, Johnson EC, Anokhin A, Bauer L, Bucholz KK, Dick DM, Hariri AR, Hesselbrock V, Kamarajan C, Kramer J, Kuperman S, Meyers JL, Nurnberger JI Jr, Schuckit M, Scott DM, Taylor RE, Tischfield J, Porjesz B, Goate AM, Edenberg HJ, Foroud T, Bogdan R, Agrawal A.  Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.  Genes Brain Behav. 2019 Jul;18(6):e12580. doi: 10.1111/gbb.12580. Epub 2019 Jun 11.

Lai D, Wetherill L, Bertelsen S, Carey CE, Kamarajan C, Kapoor M, Meyers JL, Anokhin AP, Bennett DA, Bucholz KK, Chang KK, De Jager PL, Dick DM, Hesselbrock V, Kramer J, Kuperman S, Nurnberger JI Jr, Raj T, Schuckit M, Scott DM, Taylor RE, Tischfield J, Hariri AR, Edenberg HJ, Agrawal A, Bogdan R, Porjesz B, Goate AM, Foroud T.  Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.  Genes Brain Behav. 2019 Jul;18(6):e12579. doi: 10.1111/gbb.12579. Epub 2019 Jun 4. PMCID:  PMC6612573

Aijaz A, Li M, Smith D, Khong D, LeBlon C, Fenton OS, Olabisi RM, Libutti S, Tischfield J, Maus MV, Deans R, Barcia RN, Anderson DG, Ritz J, Preti R, Parekkadan B.  Biomanufacturing for clinically advanced cell therapies.  Nat Biomed Eng. 2018 Jun;2(6):362-376. doi: 10.1038/s41551-018-0246-6. Epub 2018 Jun 11. Review. PMCID:  PMC6594100

Yu D, Sul JH, Tsetsos F, Nawaz MS, Huang AY, Zelaya I, Illmann C, Osiecki L, Darrow SM, Hirschtritt ME, Greenberg E, Muller-Vahl KR, Stuhrmann M, Dion Y, Rouleau G, Aschauer H, Stamenkovic M, Schlögelhofer M, Sandor P, Barr CL, Grados M, Singer HS, Nöthen MM, Hebebrand J, Hinney A, King RA, Fernandez TV, Barta C, Tarnok Z, Nagy P, Depienne C, Worbe Y, Hartmann A, Budman CL, Rizzo R, Lyon GJ, McMahon WM, Batterson JR, Cath DC, Malaty IA, Okun MS, Berlin C, Woods DW, Lee PC, Jankovic J, Robertson MM, Gilbert DL, Brown LW, Coffey BJ, Dietrich A, Hoekstra PJ, Kuperman S, Zinner SH, Luðvigsson P, Sæmundsen E, Thorarensen Ó, Atzmon G, Barzilai N, Wagner M, Moessner R, Ophoff R, Pato CN, Pato MT, Knowles JA, Roffman JL, Smoller JW, Buckner RL, Willsey AJ, Tischfield JA, Heiman GA, Stefansson H, Stefansson K, Posthuma D, Cox NJ, Pauls DL, Freimer NB, Neale BM, Davis LK, Paschou P, Coppola G, Mathews CA, Scharf JM; Tourette Association of America International Consortium for Genetics, the Gilles de la Tourette GWAS Replication Initiative, the Tourette International Collaborative Genetics Study, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group.  Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.  Am J Psychiatry. 2019 Mar 1;176(3):217-227. doi: 10.1176/appi.ajp.2018.18070857.

Kapoor M, Wang JC, Farris SP, Liu Y, McClintick J, Gupta I, Meyers JL, Bertelsen S, Chao M, Nurnberger J, Tischfield J, Harari O, Zeran L, Hesselbrock V, Bauer L, Raj T, Porjesz B, Agrawal A, Foroud T, Edenberg HJ, Mayfield RD, Goate A. Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism.  Transl Psychiatry. 2019 Feb 14;9(1):89. doi: 10.1038/s41398-019-0384-y. PMCID:  PMC6376002

Tabakin AL, Sadimin ET, Tereshchenko I, Kareddula A, Stein MN, Mayer T, Hirshfield KM, Kim IY, Tischfield J, DiPaola RS, Singer EA.  Correlation of Prostate Cancer CHD1 Status with Response to Androgen Deprivation Therapy: a Pilot Study.  J Genitourin Disord. 2018;2(1). pii: 1006. Epub 2018 Jul 31. PMCID: PMC6358174

McClintick JN, Tischfield JA, Deng L, Kapoor M, Xuei X, Edenberg HJ.  Ethanol Activates Immune Response In Lymphoblastoid Cells.  Alcohol. 2019 Jan 9;79:81-91. doi: 10.1016/j.alcohol.2019.01.001. [Epub ahead of print] PMCID:  PMC6616005

Wang S, Mandell JD, Kumar Y, Sun N, Morris MT, Arbelaez J, Nasello C, Dong S, Duhn C, Zhao X, Yang Z, Padmanabhuni SS, Yu D, King RA, Dietrich A, Khalifa N, Dahl N, Huang AY, Neale BM, Coppola G, Mathews CA, Scharf JM; Tourette International Collaborative Genetics Study (TIC Genetics); Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE); Tourette Association of America International Consortium for Genetics (TAAICG), Fernandez TV, Buxbaum JD, De Rubeis S, Grice DE, Xing J, Heiman GA, Tischfield JA, Paschou P, Willsey AJ, State MW.  De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.  Cell Rep. 2018 Dec 18;25(12):3544. doi: 10.1016/j.celrep.2018.12.024. No abstract available.

Sahota A, Tischfield JA, Goldfarb DS, Ward MD, Hu L. Cystinuria: genetic aspects, mouse models, and a new approach to therapy.  Urolithiasis. 2019 Feb;47(1):57-66. doi: 10.1007/s00240-018-1101-7. Epub 2018 Dec 4. PMCID: PMC6592844

Johnson EC, Tillman R, Aliev F, Meyers JL, Salvatore JE, Anokhin AP, Dick DM, Edenberg HJ, Kramer J, Kuperman S, McCutcheon VV, Nurnberger JI Jr, Porjesz B, Schuckit M, Tischfield J, Bucholz KK, Agrawal A. Exploring the relationship between polygenic risk for cannabis use, peer cannabis use, and the longitudinal course of cannabis involvement.  Addiction. 2018 Nov 26. [Epub ahead of print]

Abdulkadir M, Mathews CA, Scharf JM, Yu D, Tischfield JA, Heiman GA, Hoekstra PJ, Dietrich A.  Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort.  Biol Psychiatry. 2019 Feb 15;85(4):298-304. doi: 10.1016/j.biopsych.2018.09.011. Epub 2018 Sep 29. PMCID: PMC6342633

Edwards AC, Deak JD, Gizer IR, Lai D, Chatzinakos C, Wilhelmsen KP, Lindsay J, Heron J, Hickman M, Webb BT, Bacanu SA, Foroud TM, Kendler KS, Dick DM, Schuckit MA; Collaborative Study on the Genetics of Alcoholism (COGA).  Collaborators:  Porjesz B, Hesselbrock V, Edenberg H, Bierut L, Hesselbrock V, Edenberg HJ, Nurnberger J Jr, Foroud T, Liu Y, Kuperman S, Kramer J, Porjesz B, Bierut L, Rice J, Bucholz K, Agrawal A, Schuckit M, Tischfield J, Brooks A, Almasy L, Dick D, Goate A, Taylor R, Parsian A, Chen H. Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.  Alcohol Clin Exp Res. 2018 Oct 1. [Epub ahead of print]

Publicaitons via PubMed

1. Hu, L, Taneja, A, Zahid, H, Wang, Y, Yang, M, An, Z, Li, X, Tischfield, JA, Knight, J, Ward, MD et al.. Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria. ACS Med Chem Lett. 2024;15 (11):2005-2011. doi: 10.1021/acsmedchemlett.4c00423. PubMed PMID:39563801 PubMed Central PMC11571055
2. Li, X, Liu, J, Boreland, AJ, Kapadia, S, Zhang, S, Stillitano, AC, Abbo, Y, Clark, L, Lai, D, Liu, Y et al.. Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model. Sci Adv. 2024;10 (45):eado5820. doi: 10.1126/sciadv.ado5820. PubMed PMID:39514655 PubMed Central PMC11546823
3. Gamez-Garcia, A, Espinosa-Alcantud, M, Bueno-Costa, A, Alari-Pahissa, E, Marazuela-Duque, A, Thackray, JK, Ray, C, Berenguer, C, Kumari, P, Bech, JJ et al.. A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5. Nat Immunol. 2024;25 (12):2308-2319. doi: 10.1038/s41590-024-01995-7. PubMed PMID:39424985 PubMed Central PMC11588656
4. Green, N, Gao, H, Chu, X, Yuan, Q, McGuire, P, Lai, D, Jiang, G, Xuei, X, Reiter, JL, Stevens, J et al.. Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder. bioRxiv. 2024; :. doi: 10.1101/2024.08.02.606355. PubMed PMID:39149227 PubMed Central PMC11326171
5. Nasello, C, Poppi, LA, Wu, J, Kowalski, TF, Thackray, JK, Wang, R, Persaud, A, Mahboob, M, Lin, S, Spaseska, R et al.. Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice. Proc Natl Acad Sci U S A. 2024;121 (19):e2307156121. doi: 10.1073/pnas.2307156121. PubMed PMID:38683996 PubMed Central PMC11087812
6. Chen, AB, Yu, X, Thapa, KS, Gao, H, Reiter, JL, Xuei, X, Tsai, AP, Landreth, GE, Lai, D, Wang, Y et al.. Functional 3′-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits. bioRxiv. 2024; :. doi: 10.1101/2024.01.31.578270. PubMed PMID:38370821 PubMed Central PMC10871301
7. Prytkova, I, Liu, Y, Fernando, M, Gameiro-Ros, I, Popova, D, Kamarajan, C, Xuei, X, Chorlian, DB, Edenberg, HJ, Tischfield, JA et al.. Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons. J Neurosci. 2024;44 (16):. doi: 10.1523/JNEUROSCI.0918-23.2024. PubMed PMID:38350999 PubMed Central PMC11026340
8. Vazquez, BN, Fernández-Duran, I, Hernandez, Y, Tarighi, S, Thackray, JK, Espinosa-Alcantud, M, Kumari, P, Ianni, A, Cesaire, L, Braun, T et al.. SIRT7 and p53 interaction in embryonic development and tumorigenesis. Front Cell Dev Biol. 2023;11 :1281730. doi: 10.3389/fcell.2023.1281730. PubMed PMID:38234684 PubMed Central PMC10791984
9. Thomas, NS, Gillespie, NA, Chan, G, Edenberg, HJ, Kamarajan, C, Kuo, SI, Miller, AP, Nurnberger, JI Jr, Tischfield, J, Dick, DM et al.. A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency. Behav Genet. 2024;54 (2):151-168. doi: 10.1007/s10519-023-10170-x. PubMed PMID:38108996 PubMed Central PMC10913412
10. Wang, S, Wang, B, Drury, V, Drake, S, Sun, N, Alkhairo, H, Arbelaez, J, Duhn, C, Tourette International Collaborative Genetics (TIC Genetics), Bal, VH et al.. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD. Nat Commun. 2023;14 (1):8077. doi: 10.1038/s41467-023-43776-0. PubMed PMID:38057346 PubMed Central PMC10700338