Human genome-guided identification of memory-modulating drugs

Papassotiropoulos A, Gerhards C, Heck A, Ackermann S, Aerni A, Schicktanz N, Auschra B, Demougin P, Mumme E, Elbert T, Ertl V, et al. (2013)
Proceedings of the National Academy of Sciences of the United States of America 110(46): E4369-E4374.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Papassotiropoulos, Andreas; Gerhards, Christiane; Heck, Angela; Ackermann, Sandra; Aerni, Amanda; Schicktanz, Nathalie; Auschra, Bianca; Demougin, Philippe; Mumme, Eva; Elbert, Thomas; Ertl, VerenaUniBi; Gschwind, Leo
Abstract / Bemerkung
In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory-a trait central to posttraumatic stress disorder-and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand-receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.
Proceedings of the National Academy of Sciences of the United States of America
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Papassotiropoulos A, Gerhards C, Heck A, et al. Human genome-guided identification of memory-modulating drugs. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(46):E4369-E4374.
Papassotiropoulos, A., Gerhards, C., Heck, A., Ackermann, S., Aerni, A., Schicktanz, N., Auschra, B., et al. (2013). Human genome-guided identification of memory-modulating drugs. Proceedings of the National Academy of Sciences of the United States of America, 110(46), E4369-E4374. doi:10.1073/pnas.1314478110
Papassotiropoulos, A., Gerhards, C., Heck, A., Ackermann, S., Aerni, A., Schicktanz, N., Auschra, B., Demougin, P., Mumme, E., Elbert, T., et al. (2013). Human genome-guided identification of memory-modulating drugs. Proceedings of the National Academy of Sciences of the United States of America 110, E4369-E4374.
Papassotiropoulos, A., et al., 2013. Human genome-guided identification of memory-modulating drugs. Proceedings of the National Academy of Sciences of the United States of America, 110(46), p E4369-E4374.
A. Papassotiropoulos, et al., “Human genome-guided identification of memory-modulating drugs”, Proceedings of the National Academy of Sciences of the United States of America, vol. 110, 2013, pp. E4369-E4374.
Papassotiropoulos, A., Gerhards, C., Heck, A., Ackermann, S., Aerni, A., Schicktanz, N., Auschra, B., Demougin, P., Mumme, E., Elbert, T., Ertl, V., Gschwind, L., Hanser, E., Huynh, K.-D., Jessen, F., Kolassa, I.-T., Milnik, A., Paganetti, P., Spalek, K., Vogler, C., Muhs, A., Pfeifer, A., de Quervain, D.J.-F.: Human genome-guided identification of memory-modulating drugs. Proceedings of the National Academy of Sciences of the United States of America. 110, E4369-E4374 (2013).
Papassotiropoulos, Andreas, Gerhards, Christiane, Heck, Angela, Ackermann, Sandra, Aerni, Amanda, Schicktanz, Nathalie, Auschra, Bianca, Demougin, Philippe, Mumme, Eva, Elbert, Thomas, Ertl, Verena, Gschwind, Leo, Hanser, Edveena, Huynh, Kim-Dung, Jessen, Frank, Kolassa, Iris-Tatjana, Milnik, Annette, Paganetti, Paolo, Spalek, Klara, Vogler, Christian, Muhs, Andreas, Pfeifer, Andrea, and de Quervain, Dominique J-F. “Human genome-guided identification of memory-modulating drugs”. Proceedings of the National Academy of Sciences of the United States of America 110.46 (2013): E4369-E4374.

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Ferguson LB, Harris RA, Mayfield RD., Psychopharmacology (Berl) 235(6), 2018
PMID: 29497781
Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts.
Conrad D, Wilker S, Schneider A, Karabatsiakis A, Pfeiffer A, Kolassa S, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J-F de Quervain D, Elbert T, Kolassa IT., Psychophysiology (), 2018
PMID: 30328613
Genetic Association-Guided Analysis of Gene Networks for the Study of Complex Traits.
Greene CS, Himmelstein DS., Circ Cardiovasc Genet 9(2), 2016
PMID: 27094199
The neuroimmune transcriptome and alcohol dependence: potential for targeted therapies.
Warden A, Erickson E, Robinson G, Harris RA, Mayfield RD., Pharmacogenomics 17(18), 2016
PMID: 27918243
FASTKD2 is associated with memory and hippocampal structure in older adults.
Ramanan VK, Nho K, Shen L, Risacher SL, Kim S, McDonald BC, Farlow MR, Foroud TM, Gao S, Soininen H, Kłoszewska I, Mecocci P, Tsolaki M, Vellas B, Lovestone S, Aisen PS, Petersen RC, Jack CR, Shaw LM, Trojanowski JQ, Weiner MW, Green RC, Toga AW, De Jager PL, Yu L, Bennett DA, Saykin AJ., Mol Psychiatry 20(10), 2015
PMID: 25385369
Failed drug discovery in psychiatry: time for human genome-guided solutions.
Papassotiropoulos A, de Quervain DJ., Trends Cogn Sci 19(4), 2015
PMID: 25727774
Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.
Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen VP, Nikpay M, Erdmann J, Blankenberg S, O'Donnell C, März W, Laaksonen R, Stewart AF, Epstein SE, Shah SH, Granger CB, Hazen SL, Kathiresan S, Reilly MP, Yang X, Quertermous T, Samani NJ, Schunkert H, Assimes TL, McPherson R., Arterioscler Thromb Vasc Biol 35(7), 2015
PMID: 25977570
Computational dissection of human episodic memory reveals mental process-specific genetic profiles.
Luksys G, Fastenrath M, Coynel D, Freytag V, Gschwind L, Heck A, Jessen F, Maier W, Milnik A, Riedel-Heller SG, Scherer M, Spalek K, Vogler C, Wagner M, Wolfsgruber S, Papassotiropoulos A, de Quervain DJ., Proc Natl Acad Sci U S A 112(35), 2015
PMID: 26261317

38 References

Daten bereitgestellt von Europe PubMed Central.

Genomewide association studies and assessment of the risk of disease.
Manolio TA., N. Engl. J. Med. 363(2), 2010
PMID: 20647212
Genomewide association studies: history, rationale, and prospects for psychiatric disorders.
Psychiatric GWAS Consortium Coordinating Committee, Cichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J, Lehner T, Levinson DF, Moran A, Sklar P, Sullivan PF, Faraone S, Anney R, Buitelaar J, Elia J, Franke B, Gill M, Hakonarson H, Kent L, McGough J, Mick E, Nisenbaum L, Smalley S, Thapar A, Todd R, Todorov A, Devlin B, Daly M, Anney R, Arking D, Buxbaum JD, Chakravarti A, Cook E, Gill M, Peltonen L, Piven J, Rouleau G, Santangelo S, Schellenberg G, Scherer S, Sutcliffe J, Szatmari P, Vieland V, Kelsoe J, Sklar P, Andreassen OA, Blackwood D, Boehnke M, Breuer R, Burmeister M, Cichon S, Corvin A, Craddock N, Ferreira M, Flickinger M, Greenwood T, Guan W, Gurling H, Li J, Mick E, Moskvina V, Muglia P, Muir W, Noethen M, Nurnberger J, Purcell S, Rietschel M, Ruderfer D, Schork N, Schulze T, Scott L, Steffens M, Upmanyu R, Wienker T, Smoller J, Craddock N, Kendler K, Nurnberger J, Perlis R, Purcell S, Rietschel M, Santangelo S, Thapar A, Sullivan P, Blackwood D, Boomsma D, Breuer R, Cichon S, Coryell W, de Geus E, Hamilton S, Hoogendijk W, Kloiber S, Lawson WB, Levinson D, Lewis C, Lucae S, Martin N, McGrath P, McGuffin P, Muglia P, Muir W, Noethen M, Offord J, Penninx B, Potash JB, Rietschel M, Scheftner WA, Schulze T, Slager S, Tozzi F, Weissman MM, Willemsen AH, Wray N, Gejman P, Andreassen OA, Blackwood D, Cichon S, Corvin A, Daly M, Fanous A, Gill M, Gurling H, Holmans P, Hultman C, Kendler K, Kivikko S, Laurent C, Lencz T, Levinson D, Malhotra A, Mowry B, Noethen M, O'Donovan M, Ophoff R, Owen M, Peltonen L, Pulver A, Rietschel M, Riley B, Sanders A, Schulze T, Schwab S, Sklar P, St Clair D, Sullivan P, Suvisaari J, van den Oord E, Wray N, Wildenaver D, Daly M, Awadalla P, Devlin B, Dudbridge F, Frigessi A, Holliday E, Holmans P, Lencz T, Levinson D, Lewis C, Lin D, Moskvina V, Mowry B, Neale B, Pickering E, Posthuma D, Purcell S, Rice J, Ripke S, Schork N, Sebat J, Steffens M, Stone J, Tzeng JY, van den Oord E, Vieland V., Am J Psychiatry 166(5), 2009
PMID: 19339359
Initial impact of the sequencing of the human genome.
Lander ES., Nature 470(7333), 2011
PMID: 21307931
A glimmer of light for neuropsychiatric disorders.
Hyman SE., Nature 455(7215), 2008
PMID: 18923510
Use of genome-wide association studies for drug repositioning.
Sanseau P, Agarwal P, Barnes MR, Pastinen T, Richards JB, Cardon LR, Mooser V., Nat. Biotechnol. 30(4), 2012
PMID: 22491277

A HapMap harvest of insights into the genetics of common disease.
Manolio TA, Brooks LD, Collins FS., J. Clin. Invest. 118(5), 2008
PMID: 18451988
Analysing biological pathways in genome-wide association studies.
Wang K, Li M, Hakonarson H., Nat. Rev. Genet. 11(12), 2010
PMID: 21085203
Transcriptomic analysis of autistic brain reveals convergent molecular pathology.
Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH., Nature 474(7351), 2011
PMID: 21614001
Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder.
Holmans P, Green EK, Pahwa JS, Ferreira MA, Purcell SM, Sklar P; Wellcome Trust Case-Control Consortium, Owen MJ, O'Donovan MC, Craddock N., Am. J. Hum. Genet. 85(1), 2009
PMID: 19539887
Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
Psychiatric GWAS Consortium Bipolar Disorder Working Group, Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ Jr, Nurnberger JI, Rietschel M, Blackwood D, Corvin A, Flickinger M, Guan W, Mattingsdal M, McQuillen A, Kwan P, Wienker TF, Daly M, Dudbridge F, Holmans PA, Lin D, Burmeister M, Greenwood TA, Hamshere ML, Muglia P, Smith EN, Zandi PP, Nievergelt CM, McKinney R, Shilling PD, Schork NJ, Bloss CS, Foroud T, Koller DL, Gershon ES, Liu C, Badner JA, Scheftner WA, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, McMahon FJ, Schulze TG, Berrettini W, Lohoff FW, Potash JB, Mahon PB, McInnis MG, Zollner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Breuer R, Meier S, Strohmaier J, Witt SH, Tozzi F, Farmer A, McGuffin P, Strauss J, Xu W, Kennedy JL, Vincent JB, Matthews K, Day R, Ferreira MA, O'Dushlaine C, Perlis R, Raychaudhuri S, Ruderfer D, Lee PH, Smoller JW, Li J, Absher D, Bunny WE, Barchas JD, Schatzberg AF, Jones EG, Meng F, Thompson RC, Watson SJ, Myers RM, Akil H, Boehnke M, Chambert K, Moran J, Scolnick E, Djurovic S, Melle I, Morken G, Gill M, Morris D, Quinn E, Muhleisen TW, Degenhardt FA, Mattheisen M, Schumacher J, Maier W, Steffans M, Propping P, Nothen MM, Anjorin A, Bass N, Gurling H, Kandaswamy R, Lawrence J, McGhee K, McIntosh A, McLean AW, Muir WJ, Pickard BS, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Frozeva D, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Williamson R, Young AH, Ferrier IN, Stefansson K, Stefansson H, Porgeirsson P, Steinberg S, Gustafsson O, Bergen SE, Nimgaonkar V, Hultman C, Landen M, Lichtenstein P, Sullivan P, Schalling M, Osby U, Backlund L, Frisen L, Langstrom N, Jamain S, Leboyer M, Etain B, Bellivier F, Petursson H, Sigurđsson E, Muller-Mysok B, Lucae S, Schwarz M, Fullerton JM, Schofield PR, Martin N, Montgomery GW, Lathrop M, Oskarsson H, Bauer M, Wright A, Mitchell PB, Hautzinger M, Reif A, Kelsoe JR, Purcell SM., Nat. Genet. 43(10), 2011
PMID: 21926972
Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.
Stergiakouli E, Hamshere M, Holmans P, Langley K, Zaharieva I; deCODE Genetics; Psychiatric GWAS Consortium, Hawi Z, Kent L, Gill M, Williams N, Owen MJ, O'Donovan M, Thapar A, Faraone SV, Neale BM, Ripke S, Daly M, Medland SE, Asherson P, Franke B, Steinhausen HC, Lesch KP, Freitag C, Reif A, Renner TJ, Nguyen TT, Romanos M, Romanos J, Walitza S, Schafer H, Warnke A, Meyer J, Palmason H, Buitelaar J, Vasquez AA, Lambregts-Rommelse N, Anney RJ, Sergeant J, Roeyers H, Mick E, Biederman J, Doyle A, Smalley S, Loo S, Hakonarson H, Elia J, Todorov A, Miranda A, Mulas F, Ebstein R, Rothenberger A, Banaschewski T, Oades R, Sonuga-Barke E, McGough J, Nisenbaum L, Middleton F, Hu X, Nelson S., Am J Psychiatry 169(2), 2012
PMID: 22420046
Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.
O'Dushlaine C, Kenny E, Heron E, Donohoe G, Gill M, Morris D; International Schizophrenia Consortium, Corvin A, Morris DW, O'Dushlaine CT, Kenny E, Quinn EM, Gill M, Corvin A, O'Donovan MC, Kirov GK, Craddock NJ, Holmans PA, Williams NM, Georgieva L, Nikolov I, Norton N, Williams H, Toncheva D, Milanova V, Owen MJ, Hultman CM, Lichtenstein P, Thelander EF, Sullivan P, McQuillin A, Choudhury K, Datta S, Pimm J, Thirumalai S, Puri V, Krasucki R, Lawrence J, Quested D, Bass N, Gurling H, Crombie C, Fraser G, Kuan SL, Walker N, St Clair D, Blackwood DH, Muir WJ, McGhee KA, Pickard B, Malloy P, Maclean AW, Van Beck M, Wray NR, Visscher PM, Macgregor S, Pato MT, Medeiros H, Middleton F, Carvalho C, Morley C, Fanous A, Conti D, Knowles JA, Ferreira CP, Macedo A, Azevedo MH, Pato CN, Stone JL, Ruderfer DM, Ferreira MA, Purcell SM, Stone JL, Chambert K, Ruderfer DM, Kuruvilla F, Gabriel SB, Ardlie K, Daly MJ, Scolnick EM, Sklar P., Mol. Psychiatry 16(3), 2010
PMID: 20157312
PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.
de Quervain DJ, Kolassa IT, Ackermann S, Aerni A, Boesiger P, Demougin P, Elbert T, Ertl V, Gschwind L, Hadziselimovic N, Hanser E, Heck A, Hieber P, Huynh KD, Klarhofer M, Luechinger R, Rasch B, Scheffler K, Spalek K, Stippich C, Vogler C, Vukojevic V, Stetak A, Papassotiropoulos A., Proc. Natl. Acad. Sci. U.S.A. 109(22), 2012
PMID: 22586106
A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans.
de Quervain DJ, Kolassa IT, Ertl V, Onyut PL, Neuner F, Elbert T, Papassotiropoulos A., Nat. Neurosci. 10(9), 2007
PMID: 17660814

McGaugh JL., 2003
Post-traumatic stress disorder, hormones, and memory.
Pitman RK., Biol. Psychiatry 26(3), 1989
PMID: 2545287
A genetic variation of the noradrenergic system is related to differential amygdala activation during encoding of emotional memories.
Rasch B, Spalek K, Buholzer S, Luechinger R, Boesiger P, Papassotiropoulos A, de Quervain DJ., Proc. Natl. Acad. Sci. U.S.A. 106(45), 2009
PMID: 19826083


Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood.
Verster JC, Volkerts ER, van Oosterwijck AW, Aarab M, Bijtjes SI, De Weert AM, Eijken EJ, Verbaten MN., J. Allergy Clin. Immunol. 111(3), 2003
PMID: 12642847
Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance.
Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, Sukenik E, Harris AG., Arch. Intern. Med. 157(20), 1997
PMID: 9361576
Sedation and memory: studies with a histamine H-1 receptor antagonist.
Turner C, Handford AD, Nicholson AN., J. Psychopharmacol. (Oxford) 20(4), 2006
PMID: 16401664
Neutral and emotional episodic memory: global impairment after lorazepam or scopolamine.
Kamboj SK, Curran HV., Psychopharmacology (Berl.) 188(4), 2006
PMID: 17047934
Effects of melatonin on human mood and performance.
Lieberman HR, Waldhauser F, Garfield G, Lynch HJ, Wurtman RJ., Brain Res. 323(2), 1984
PMID: 6525511
Morphine use after combat injury in Iraq and post-traumatic stress disorder.
Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL., N. Engl. J. Med. 362(2), 2010
PMID: 20071700
Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.
Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG; BIRAC Consortium, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP; YEAR Consortium, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM., Nat. Genet. 42(6), 2010
PMID: 20453842


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