Ament, Seth | University of Maryland School of Medicine

Academic Title:

Associate Professor

Primary Appointment:

Psychiatry

Additional Title:

Associate Professor, Institute for Genome Sciences; Associate Professor, Maryland Psychiatric Research Center

Email:

sament@som.umaryland.edu

Location:

670 West Baltimore Street Room 3182 Baltimore, MD 21201

Phone (Primary):

(410) 706-5681

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Education and Training

University of Illinois at Urbana-Champaign, PhD, Neuroscience, 2010
A.B. Harvard University, A.B., Biology, 2003

Biosketch

My research focuses on genetic and genomic studies of the brain and brain disorders through four strategies:

genome sequencing studies to identify rare mutations that increase risk for brain disorders, and functional studies of these mutations in human stem cells and animal models;
single-cell transcriptomics and epigenomics studies to characterize the diversity of cell types in the brain and how these populations of cells are altered in brain disorders;
molecular and computational systems biology studies integrating GWAS and functional genomics data from the mammalian brain to characterize disease-perturbed gene networks and multi-scale disease mechanisms; and
translational studies designed to leverage genomic data for the development of clinically useful biomarkers and novel therapeutic targets.

Ongoing studies in the lab apply these approaches to mood disorders, schizophrenia, substance use disorders, Huntington's disease, neuroinflammation, and hearing loss. Our work is highly collaborative, both locally and as part of large consortia, including the BRAIN Initiative Cell Census Network and the Whole Genome Sequencing of Psychiatric Disorders consortium.

Research/Clinical Keywords

Bipolar disorder; schizophrenia; genetics; genomics; systems biology; stem cells; neuron; brain; behavior, mood disorders, schizophrenia, substance use disorders, Huntington's disease, neuroinflammation, hearing loss

Highlighted Publications

Rare Variants in Neuropsychiatry

Hasin N., Riggs L.M., Shekhtman T., Ashworth J., Lease R., Oshone R.T., Humphries E., Badner J., Thompson P., Glahn D.C., Craig D.W., Edenberg H.J., Gershon E., McMahon F.J., Nurnberger J.I., Zandi P.P., Kelsoe J.R., Roach J.C., Gould T.D., and Ament S.A. (2021) Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder. medRxiv. doi:10.1101/2021.06.02.21258261

Ament S.A., Szelinger S., Glusman G., Ashworth J., Hou L., Akula N., Shekhtman T., Badner J.A., Brunkow M.E., Mauldin D.E., Stittrich A.B., Rouleau K., Detera-Wadleigh S., Nurnberger J.I., Edenberg H.J., Gershon E.S., Schork N.J., The Bipolar Genome Study, Price N.D., Gelinas R., Hood L., Craig D.W., McMahon F.J., Kelsoe J.R., and Roach J.C. (2015) Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci USA. 112(11):3576-3581.

Single-Cell Genomics

Herb B.R., Glover H.J., Bhaduri A., Casella A.M., Bale T.L., Kriegstein A.R., Doege C.A., Ament S.A. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the prenatal human hypothalamus. bioRxiv. https://doi.org/10.1101/2021.07.20.453090

Adkins R.S. et al. (along with the BRAIN Initiative Cell Census Network, including Ament S.A.). A multimodal cell census and atlas of the mammalian primary motor cortex. bioRxiv. doi: https://doi.org/10.1101/2020.10.19.343129

Ziffra R.S., Kim C.N., Wilfert A., Turner T.N., Haeussler M., Casella A.M., Przytycki P.F., Kreimer A., Pollard K.S., Ament S.A., Eichler E.E., Ahituv N., Nowakowski T.J. Single cell epigenomic atlas of the developing human brain and organoids. bioRxiv. doi: https://doi.org/10.1101/2019.12.30.891549

Malaiya S.*, Cortes-Gutierrez M.*, Herb B.R., Coffey S.R., Legg S.R.W., Cantle B.P., Carroll J.B., Ament S.A. Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations. J Neurosci. JN-RM-2074-20; DOI: https://doi.org/10.1523/JNEUROSCI.2074-20.2021.

Network Biology

Casella A.M., Colantuoni C., Ament S.A. Regulome-wide association study identifies enhancer properties associated with risk for schizophrenia. bioRxiv. https://doi.org/10.1101/2021.06.14.448418

Funk C.C.*, Casella A.M.*, Jung S., Richards M., Rodriguez A., Shannon P., Donovan R., Heavner B., Chard K., Xiao Y., Glusman G., Erleskin-Taner N., Golde T., Toga A., Hood L., Van Horn J.D., Kesselman C., Foster I., Madduri R., Price N.D., Ament S.A. (2020) Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data Across 27 Tissue Types. Cell Reports. 32(7):108029.

Pearl J.R., Colantuoni C., Bergey D.E., Funk C.C., Basu B., Casella A.M., Oshone R., Shannon P., Hood L., Price N.D., Ament S.A. (2019) Genome-scale transcriptional regulatory network models of psychiatric and neurodegenerative disorders. Cell Systems. 8(2):122-135.e7

Ament S.A.*, Pearl J.R.*, Bragg R.M., Skene P., Coffey S.R., Plaisier C.L., Wheeler V.C., MacDonald M.E., Baliga N.S., Rosinski J., Hood L.E., Carroll J.B., and Price N.D. (2018) Genome-scale transcriptional regulatory network models for the mouse and human striatum predict roles for SMAD3 and other transcription factors in Huntington's disease. Mol. Systems Biol. 14(3):e7435.

Peer-reviewed journal articles

Note: For all publications, * is used to indicate equal contributions, while # is used to indicate corresponding authors.

Ament S.A., Bullis R., Hanlon R.T., and Mensinger A. (1997) Righting response and escape response in Opsanus tau are temperature dependent. Biol Bull 193:265-266.

Hanlon R.T., Ament S.A., and Gabr H. (1999) Behavioral aspects of sperm competition in cuttlefish, Sepia officinalis (Sepioidea: Cephalopoda). Marine Biol 134:719-728.

Shashar N., Borst D.T., Ament S.A., Saidel W.M., Smolowitz R.M., and Hanlon R.T., (2001) Polarization reflecting iridophores in the arms of the squid Loligo pealeii. Biol Bull 201:267-268.

Smith A.B. et al. (along with the Honeybee Genome Sequencing Consortium, including Ament S.A.] (2006) Insights into social insects from the genome of the honeybee Apis mellifera. Nature 443:931-49.

Kunieda T.*, Fujiyuki T.*, Kucharski R.*, Foret S.*, Ament S.A.*, Toth A.L.*, Ohashi K., Takeuchi H., Kamikouchi A., Kage E., Morioka M., Beye M., Kubo T., Robinson G.E., and Maleszka R. (2006) Carbohydrate metabolism genes and pathways in insects: insights from the honey bee genome. Insect Mol Biol 15:563-576.

Ament S.A., Corona M., Pollock H.S., and Robinson G.E. (2008) Insulin signaling is involved in the regulation of worker division of labor in honey bee colonies. Proc Natl Acad Sci USA, 105:4226-4231.

Brockmann A. Annangudi P., Richmond T.A., Ament S.A., Xie F., Southey B.R., Rodriguez-Zas S.R., Sweedler J.V., and Robinson G.E. (2009) Quantitative peptidomics reveal brain peptide signatures of behavior. Proc Natl Acad Sci USA. 106:2383-2388.

Ament S.A., Wang Y., and Robinson G.E. (2010) Nutritional regulation of worker division labor in honey bee colonies: a systems perspective. Wiley Interdiscipl Rev: Systems Biol Med. 2(5):566-576.

Ament S.A., Velarde R.A., Kolodkin M., Moyse D., and Robinson G.E. (2011) Neuropeptide Y-like signaling and nutritionally-mediated gene expression and behavior in the honey bee. Insect Mol Biol. 20(3):335-345.

Ament S.A., Chan Q.W., Wheeler M.W., Nixon S.E., Johnson S.P., Rodriguez-Zas S.R., Foster L.J., and Robinson G.E. (2011) Mechanisms of stable lipid loss in a social insect. J Exp Biol. 214:3808-3821.

Chandrasekaran S., Ament S.A., Eddy J.A., Rodriguez-Zas S.R., Schatz B.R., Price N.D., and Robinson G.E. (2011) Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states. Proc Natl Acad Sci USA. 108:18020-18025.

Ament S.A.*, Wang Y.*, Chen C.-C., Blatti C., Hong F., Negre N., White K.P., Rodriguez-Zas S.L., Mizzen C.A., Sinha S., Zhong S., and Robinson G.E. (2012) The transcription factor ultraspiracle influences honey bee social behavior and behavior-related gene expression. PLoS Genet. 8(3):e1002596.

Ament S.A.*, Blatti C.*, Alaux C.*, Wheeler M.W., Toth A.L., Le Conte Y., Hunt G.J., Guzmán-Novoa E., DeGrandi-Hoffman G., Uribe-Rubio J.L., Amdam G.V., Page R.E., Rodriguez-Zas S.L, Robinson G.E. and Sinha S. (2012) New meta-analysis tools reveal common transcriptional regulatory basis for multiple determinants of behavior. Proc Natl Acad Sci USA. 109:E1801-E1810.

Greenberg J., Xia J., Zhou X., Thatcher S.R., Ament S.A., Newman T.C., Green P.J., Zhang W., Robinson G.E., and Ben-Shahar Y. (2012) Behavioral plasticity in honey bees is associated with differences in brain microRNA transcriptome. Genes Brain Behav. 11(6):660-670.

Ko Y.*, Ament S.A.*, Caballero J., Earls J.C., Hood L., Price N.D. (2013) Cell-type specific genes show striking and distinct patterns of spatial expression in the mouse brain. Proc Natl Acad Sci USA. 110(8):3095-3100.

Wheeler M.M., Ament S.A., Rodriguez-Zas S.M., and Robinson G.E. (2013) Brain gene expression changes elicited by peripheral vitellogenin knockdown in the honey bee. Insect Mol Biol. 22:562-573.

Brownstein C.A., Beggs A.H., Homer N., Merriman B., Yu T.W., Flannery K.C., DeChene E.T., Towne M.C., Savage S.K., Price E.N., Holm I.A., Luquette L.J., Lyon E., Majzoub J., Neupert P., McCallie D., Szolovits P., Willard H.F., Mendelsohn N.J., Temme R., Finkel R.S., Yum S.W., Medne L., Sunyaev S.R., Adzhubey I., Cassa C.A., De Bakker P.I.W., Duzkale H., Dworzyński P., Fairbrother W., Francioli L., Funke B.H., Giovanni M.A., Handsaker R.E., Lage K., Lebo M.S., Lek M., Leshchiner I., Macarthur D.G., Rehm H.L., Soemedi R., Stitziel N.O., Vestecka S., Supper J., Gugenmus C., Klocke B., Hahn A., Schubach M., Menzel M., Biskup S., Freisinger P., Deng M., Braun M., Perner S., Smith R.J.H., Andorf J.L., Huang J., Ryckman K., Sheffield V.C., Stone E.M., Bair T., Black-Ziegelbein E.A., Braun T.A., Darbro B., DeLuca A.P., Kolbe D.L., Scheetz T.E., Shearer A.E., Sompallae R., Wang K., Bassuk A.G., Edens E,, Mathews K., Moore S.A., Shchelochkov O.A., Trapane P., Bossler A., Campbell C.A., Heusel J.W., Kwitek A., Maga T., Panzer K., Wassink T., Van Daele D., Azaiez H., Booth K., Meyer N., Segal M.M., Williams M.S., Tromp G., White P., Corsmeier D., Fitzgerald-Butt S., Herman G., Lamb-Thrush D., McBride K.L., Newsom D., Pierson C.R., Rakowsky A.T., Maver A., Lovrečić L., Palandačić A., Peterlin B., Torkamani A., Wedell A., Huss M., Alexeyenko A., Lindvall J.M., Magnusson M., Nilsson D., Stranneheim H., Taylan F., Gilissen C., Hoischen A., Van Bon B., Yntema H., Nelen M., Zhang W., Sager J., Zhang L., Blair K., Kural D., Cariaso M., Lennon G.G., Javed A., Agrawal S., Ng P.C., Sandhu K.S., Krishna S., Veeramachaneni V., Isakov O., Halperin E., Friedman E., Shomron N., Glusman G., Roach J.C., Caballero J., Cox H.C., Mauldin D., Ament S.A., Rowen L., Richards D.R., San Lucas F.A., Gonzalez-Garay M.L., Caskey C.T., Bai Y., Huang Y., Fang F., Zhang Y., Wang Z., Barrera J., Garcia-Lobo J.M., González-Lamuño D., Llorca J., Rodriguez M.C., Varela I., Reese M.G., De La Vega F.M., Kiruluta E., Cargill M., Hart R.K., Sorenson J.M., Lyon G.J., Stevenson D.A., Bray B.E., Moore B.M., Eilbeck K., Yandell M., Zhao H., Hou L., Chen X., Yan X., Chen M., Li C., Yang C., Gunel M., Li P., Kong Y., Alexander A.C., Albertyn Z.I., Boycott K.M., Bulman D.E., Gordon P.M.K., Innes A.M., Knoppers B.M., Majewski J., Marshall C.R., Parboosingh J.S., Sawyer S.L., Samuels M.E., Schwartzentruber J., Kohane I.S., Margulies D.M. (2014) An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results: The CLARITY Challenge. Genome Biol. 15(3):R53.

Glusman G., Dhankani V., Robinson M., Farrah T., Mauldin D.E., Severson A., Stittrich A.B., Ament S.A., Roach J.C., Brunkow M.E., Bodian D.L., Vockley J.G., Shmulevich I., Niederhuber J.I., and Hood L. (2015) Identification of copy number variants in whole-genome data using Reference Coverage Profiles. Front Genet. 6:45.

Wheeler M.M., Ament S.A., Rodriguez-Zas S.M., Southey B., and Robinson G.E. (2015) Diet and endocrine effects on behavioral maturation-related gene expression in the pars intercerebralis of the honey bee brain. J Exp Biol. 218:4005-4014.

Bragg R.M., Coffey S.R., Weston R.M., Ament S.A., Cantle J.P., Minnig S., Funk C.C., Shuttleworth D.D., Woods E.L., Sullivan B.R., Jones L., Glickenhaus A., Anderson J.S., Anderson M.D., Dunnett S.B., Wheeler V.C., MacDonald M.E., Brooks S.P., Price N.D., and Carroll J.B. (2017) Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.Htt^Q111/+ model of Huntington's disease. Scientific Reports. 7:41570.

Ament A.*, Pearl J.R.*, Grindeland A.*, St. Claire J., Earls J.C., Kovalenko M., Gillis T., Mysore J., Gusella J.F., Lee J.M., Kwak S., Howland D., Lee M., Baxter D., Scherler K., Wang K., Geman D., Carroll J.B., MacDonald M.E., Goodman N., Carlson G., Wheeler V.C., Price N.D., and Hood L.E. (2017) High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington’s disease CAG knock-in mice across multiple genetic backgrounds. Human Mol Genet. 26(5):913-922.

Bruce H.A., Kochunov P., Paciga S.A., Hyde C.L., Chen X., Xie Z., Zhang B., Xi H.S., O’Donnell P., Whelan C., Schubert C.R., Bellon A., Ament S.A., Shukla D.K., Du X., Rowland L.M., O’Neill H., Hong L.E. (2017) Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia. Genes Brain Behav. 16(5):515-521.

Coffey S.R., Bragg R.M., Minnig S., Ament S.A., Glickenhaus A., Shelnut D., Carrillo J.M., Shuttleworth D.D., Rodier J.-A., Noguchi K., Bennett C.F., Price N.D., Kordasiewicz J.B., Carroll J.B. (2017) Peripheral Htt silencing does not ameliorate central signs of disease in the B6.Htt^Q111/+ mouse model of Huntington’s disease. PLoS One. 12(4): e0175968.

Ryan M., Kochunov P., Rowland L.M., Mitchell B.D., Wijtenburg S.A., Fieremans E., Veraart J., Novikov D.S., Du X., Adhikari B., Fisseha F., Bruce H., Chiappelli J., Sampath H., Ament S., O'Connell J., Shuldiner A.R., Hong L.E. (2017) Lipid Metabolism, Abdominal Adiposity, and Cerebral Health in the Amish. 25(11):1876-1880.

Ament S.A.*, Pearl J.R.*, Bragg R.M., Skene P., Coffey S.R., Plaisier C.L., Wheeler V.C., MacDonald M.E., Baliga N.S., Rosinski J., Hood L.E., Carroll J.B., and Price N.D. (2018) Transcriptional regulatory networks underlying gene expression changes in Huntington's disease. Systems Biol. 14(3):e7435.

Glahn D.C., Nimgaonkar V.L., Raventós H., Contreras J., McIntosh A.M., Thomson P.A., Jablensky A., McCarthy N.S., Blackburn N.B., Peralta J.M., Knowles E.M., Mathias S.R., Ament S.A., McMahon F.J., Gur R.C., Bucan M., Curran J.E., Almasy L., Gur R.E., Blangero J. (2019) Rediscovering the Value of Families for Psychiatric Genetics Research. Molecular Psychiatry. 24(4):523-535.

Budde M., Friedrichs S., Alley-Rodriguez N., Ament S.A., Badner J.A., Berrettini W.H., Byerley W., Cichon S., Comes A.L., Coryell W., Craig D.W., Degenhardt F., Edenberg H.J., Foroud T., Forstner A.J., Frank J., Gershon E.S., Goes F.S., Greenwood T.A., Hipolito M., Hood L., Koller D.L., Lawson W.B., Liu C., McInnis M.G., McMahon F.J., Meier S.M., Mühleisen T.W., Nievergelt C.M., Nurnberger J.I., Nwulia E.A., Potash J.B., Quarless D., Rice J., Roach J.C., Scheftner W.A., Schork N.J., Shekhtman T., Shilling P.D., Streit F.S., Strohmaier J., Szelinger S., Treutlein J., Witt S.H., Zandi P.P., Bickeböller H,, Falkai P.G., Kelsoe J.R., Nöthen M.M., Rietschel M., Schulze T.G., Malzahn D. (2019) Efficient genomic region-based testing uncovers genetic risk factors for inter-episode functional outcome in bipolar disorder. European Journal of Neuropsychiatry. 29(1):156-170.

Bruce H.A., Kochunov P., Mitchell B., Strauss K.A., Ament S.A., Rowland L.M., Du X., Fisseha F., Kavita T., Chiappelli J., Wisner K., Sampath H., Chen S., Kvarta M.D., Seneviratne C., Postolache T.T., Bellon A., McMahon F.J., Shuldiner A., Hong L.E. (2019) Clinical and Genetic Validity of Quantitative Bipolarity. Transl. 9(1):228

Chan J.C., Morgan C.P., Leu N.A., Shetty A., Cisse Y.M., Nugent B.M., Morrison K.E., Jašarević E., Huang W., Kanyuch N., Rodgers A.B., Bhanu N.V., Berger D., Garcia5 B.A., Ament S.A., Kane M., Epperson C.M., Bale T.L. (2020) Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment. Nat Commun. 11:1499.

Funk C.C.*, Casella A.M.*, Jung S., Richards M., Rodriguez A., Shannon P., Donovan R., Heavner B., Chard K., Xiao Y., Glusman G., Erleskin-Taner N., Golde T., Toga A., Hood L., Van Horn J.D., Kesselman C., Foster I., Madduri R.#, Price N.D.#, Ament S.A.# Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data Across 27 Tissue Types. Cell Reports. 32 (7): 108029.

Kalra G., Milon B., Casella A.M., Song Y., Herb B.R., Rose K.P., Hertzano R., Ament S.A. (2020) Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. PLoS Genet. 16(9): e1009025.

Morgan C.P., Shetty A.C., Chan J.C., Berger D.S., Ament S.A., Epperson C.N., Bale T.L. (2020) A within- and between-subject modeling of the human sperm transcriptome identifies dynamic and stress-responsive sncRNAs. Scientific Reports. 10(1):1-20.

Bruce H., Kochunov P., Chiappelli J., Savransky, T., Scarino K., Sewell J., Marshall W., Kvarta M., McMahon F.J., Ament S.A., Postolache T., O’Connell J., Shuldiner A., Mitchell B., Hong L.E. (2021) Genetic vs. Stress and Mood Determinants of Sleep in the Amish. Am J Med Genet B: Neuropsych Genet.

Kvarta M., Bruce H., Chiappelli J., Hare S., Dr. Goldwaser E., Sewell J., Sampath H., Lightner S., Marshall W., Hatch K., Humphries E., Ament S., Shuldiner A., Mitchell B., McMahon F., Kochunov P., Hong L.E. (2021) Multidimensional Stress vs. Genetics in Depression. Translational Psychiatry. 11(1):254.

Orvis J., Gottfried B., Kancherla J., Adkins R.S., Song Y., Dror A.A., Olley D., Rose K., Chrysostomou E., Kelly M.C., Milon B., Matern M.S., Azaiez H., Herb B., Colantuoni C., Carter R.L., Ament S.A., Kelley M.W., White O., Corrada Bravo H., Mahurkar A., Hertzano R. gEAR: gene Expression Analysis Resource portal for community-driven, multi-omic data exploration. Nat Methods. 18(8):843-844. doi: 10.1038/s41592-021-01200-9

Bakken T.E., Jorstad N.L., Hu Q., Lake B.B., Tian W., Kalmbach B.E., Crow M., Hodge R.D., F.M., Sorensen S.A., Eggermont J., Yao Z., Aevermann B.D., Aldridge A.I., Bartlett A., Bertagnolli D., Casper T., Castanon R.G., Crichton K., Daigle T.L., Dalley R., Dee N., Dembrow N., Diep D., Ding S.-L., Dong W., Fang R., Fischer S., Goldman M., Goldy J., Graybuck L.T., Herb B.R., Hou X., Kancherla J., Kroll M., Lathia K., van Lew B., Li Y.E., Liu C.S., Liu H., Mahurkar A., McMillen D., Miller J.A., Moussa M., Nery J.R., Orvis J., Owen S., Palmer C.R., Pham T., Plongthongkum N., Poirion O., Reed N.M., Rimorin C., Rivkin A., Romanow W.J., Sedeño-Cortés A.E., Siletti K., Somasundaram S., Sulc J., Tieu M., Torkelson A., Tung H., Wang X., Xie F., Yanny A.M., Zhang R., Ament S.A., Corrada Bravo H., Chun J., Dobin A., Gillis J., Hertzano R., Hof P.R., Höllt T., Horwitz G.D., Keene C.D., Kharchenko P.V., Ko A.L., Lelieveldt B.P., Luo C., Mukamel E.A., Preissl S., Regev A., Ren B., Scheuermann R.H., Smith K., Spain W.J., White O.R., Koch C., Hawrylycz M., Tasic B., Macosko E.Z., McCarroll S.A., Ting J.T., Zeng H., Zhang K., Feng G., Ecker J.R., Linnarsson S., Lein E.S. Comparative cellular analysis of motor cortex in human, marmoset, and mouse. In press. (Preprint: bioRxiv. https://doi.org/10.1101/2020.03.31.016972)

Ziffra R.S., Kim C.N., Wilfert A., Turner T.N., Haeussler M., Casella A.M., Przytycki P.F., Kreimer A., Pollard K.S., Ament S.A., Eichler E.E., Ahituv N., Nowakowski T.J. Single cell epigenomic atlas of the developing human brain and organoids. In press.

Adkins R.S. et al. (along with the BRAIN Initiative Cell Census Network, including Ament S.A.). A multimodal cell census and atlas of the mammalian primary motor cortex. In press.

Yao Z.*, Liu H.*, Xie F.*, Fischer S.*, et al (along with the BRAIN Initiative Cell Census Network, including Ament S.A.). An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types. In press.

Psychiatric Genetics

Psychiatric disorders such as schizophrenia and bipolar disorder are strongly familial, with 8-10-fold relative risk in the first-degree relatives of probands. In the last few years, genoome-wide association studies have revealed >100 well-supported risk loci for psychiatric disorders, but the mechanisms by which these risk loci influence disease remain elusive, for at least two reasons. First, the effects of individual loci on risk for disease are very small (<1% relative risk). Second, most of the causal variants are non-coding, making it more difficult to determine their target genes.

Identifying rare risk variants can help characterize disease mechanisms, since these variants may have larger effects on disease risk and clearer effects on gene function than common variants discovered through GWAS. I was the lead author on one of the first whole-genome sequencing studies of bipolar disorder, identifying an enrichment of rare variants in neuronal ion channels (Ament et al., PNAS 2015). My lab is affiliated with several consortia generating large exome and genome sequencing datasets related to psychiatric disorders, including the Bipolar Genome Study, the Bipolar Sequencing Consortium, and the Anabaptist Sequencing Consortiun. Locally, we collaborate with the Program in Personalized and Genomic Medicine on genetics studies involving the Amish. The goal of all these studies is to identify rare variants, genes, and gene networks that influence risk for psychiatric disorders, as well as neurocognitive and neuroimaging endophenotypes.

Transcriptional Regulatory Networks in the Mammalian Brain

Interpreting genomic data in the context of biological networks is another powerful strategy to discover disease mechanisms. We use cutting-edge informatics tools to analyze high-throughput genomic data in order to develop hypotheses about mechanisms of brain diseases. Recently, we have developed methods to reconstruct gene regulatory networks in the human and mouse brain, leveraging sequence motifs, epigenomic and transcriptomic data to predict the tissue-specific binding sites and target genes for hundreds of transcription factors.

We are applying these methods to predict identify master regulator TFs in psychiatric and neurodegenerative diseases. We have validated several of these hypotheses through ChIP-seq and lentiviral overexpression of TFs in animal and cellular models, and using CRISPR/Cas9 genome editing. We are eager to collaborate with experimental groups generating new trancsriptomics and epigenomic datasets. Current projects aim to elucidate gene regulatory networks in psychiatric disorders, Huntington's disease, hearing loss, and brain development.

Stem Cells

Patient-derived, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons are a promising system in which to characterize phenotypes associated with the genetic variation underlying human disease. In collaboration with Elliot Hong (Psychiatry) and Francis McMahon (NIMH), my lab is developing a resource of iPSCs from Amish families with psychiatric disorders. These families have been extensively characterized for neuroimaging and neurocognitive phenotypes, creating a unique cohort in which to link genetic variation to cellular, brain, and behavior phenotypes.

We will use these cell lines to test two hypotheses emerging from psychiatric genetics and systems biology studies. First, we hypothesize that psychiatric disorders involve neurodevelopmental changes in gene regulation. Second, we hypothesize that psychiatric disorders involve synaptic changes inducing neuronal hyperexcitability. Both mechanisms are predicted to alter the structure and function of the adult brain, perhaps in subtle ways.We will test each hypothesis by characterizing the functions of specific risk variants found in Amish families.

nemoarchive.org

Neuroscience Multi-Omic Archive
NeMO Analytics

Single-Cell Opioid Responses in the Context of HIV Consortium (scorch.igs.umaryland.edu)

Ament Lab Website (amentlab.org)

Seth A. Ament, PhD