Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Max Lam; Chen Chia-Yen; Xia Yan; W. David Hill; Joey W. Trampush; Jin Yu; Emma Knowles; Gail Davies; Eli Stahl; Laura Huckins; David C. Liewald; Srdjan Djurovic; Ingrid Melle; Andrea Christoforou; Ivar Reinvang; Pamela DeRosse; Astri J. Lundervold; Vidar M. Steen; Thomas Espeseth; Katri Räikkönen; Elisabeth Widen; Aarno Palotie; Johan G. Eriksson; Ina Giegling; Bettina Konte; Annette M. Hartmann; Panos Roussos; Stella Giakoumaki; Katherine E. Burdick; Antony Payton; William Ollier; Ornit Chiba-Falek; Deborah K. Koltai; Anna C. Need; Elizabeth T. Cirulli; Aristotle N. Voineskos; Nikos C. Stefanis; Dimitrios Avramopoulos; Alex Hatzimanolis; Nikolaos Smyrnis; Robert M. Bilder; Nelson A. Freimer; Tyrone D. Cannon; Edythe London; Russell A. Poldrack; Fred W. Sabb; Eliza Congdon; Emily Drabant Conley; Matthew A. Scult; Dwight Dickinson; Richard E. Straub; Gary Donohoe; Derek Morris; Aiden Corvin; Michael Gill; Ahmad R. Hariri; Daniel R. Weinberger; Neil Pendleton; Panos Bitsios; Dan Rujescu; Jari Lahti; Stephanie Le Hellard; Matthew C. Keller; Ole A. Andreassen; Ian J. Deary; David C. Glahn; Liu Chunyu; Anil K. Malhotra; Todd Lencz

doi:10.1038/s41386-021-01023-4

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Max Lam, Chen Chia-Yen, Xia Yan, W. David Hill, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, Eli Stahl, Laura Huckins, David C. Liewald, Srdjan Djurovic, Ingrid Melle, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri RäikkönenElisabeth Widen, Aarno Palotie, Johan G. Eriksson, Ina Giegling, Bettina Konte, Annette M. Hartmann, Panos Roussos, Stella Giakoumaki, Katherine E. Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K. Koltai, Anna C. Need, Elizabeth T. Cirulli, Aristotle N. Voineskos, Nikos C. Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Nikolaos Smyrnis, Robert M. Bilder, Nelson A. Freimer, Tyrone D. Cannon, Edythe London, Russell A. Poldrack, Fred W. Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A. Scult, Dwight Dickinson, Richard E. Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R. Hariri, Daniel R. Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C. Keller, Ole A. Andreassen, Ian J. Deary, David C. Glahn, Liu Chunyu, Anil K. Malhotra, Todd Lencz

Research output: Contribution to journal › Article › peer-review

Abstract

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Original language	Undefined/Unknown
Journal	Neuropsychopharmacology
Early online date	25 May 2021
DOIs	https://doi.org/10.1038/s41386-021-01023-4
Publication status	E-pub ahead of print - 25 May 2021

Keywords

LBC1936
heritable quantitative trait

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LamEtalN2021identifyingNootropicFinal published version, 4.17 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

Lam, M., Chia-Yen, C., Yan, X., Hill, W. D., Trampush, J. W., Yu, J., Knowles, E., Davies, G., Stahl, E., Huckins, L., Liewald, D. C., Djurovic, S., Melle, I., Christoforou, A., Reinvang, I., DeRosse, P., Lundervold, A. J., Steen, V. M., Espeseth, T., ... Lencz, T. (2021). Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Neuropsychopharmacology. https://doi.org/10.1038/s41386-021-01023-4

Lam, Max ; Chia-Yen, Chen ; Yan, Xia ; Hill, W. David ; Trampush, Joey W. ; Yu, Jin ; Knowles, Emma ; Davies, Gail ; Stahl, Eli ; Huckins, Laura ; Liewald, David C. ; Djurovic, Srdjan ; Melle, Ingrid ; Christoforou, Andrea ; Reinvang, Ivar ; DeRosse, Pamela ; Lundervold, Astri J. ; Steen, Vidar M. ; Espeseth, Thomas ; Räikkönen, Katri ; Widen, Elisabeth ; Palotie, Aarno ; Eriksson, Johan G. ; Giegling, Ina ; Konte, Bettina ; Hartmann, Annette M. ; Roussos, Panos ; Giakoumaki, Stella ; Burdick, Katherine E. ; Payton, Antony ; Ollier, William ; Chiba-Falek, Ornit ; Koltai, Deborah K. ; Need, Anna C. ; Cirulli, Elizabeth T. ; Voineskos, Aristotle N. ; Stefanis, Nikos C. ; Avramopoulos, Dimitrios ; Hatzimanolis, Alex ; Smyrnis, Nikolaos ; Bilder, Robert M. ; Freimer, Nelson A. ; Cannon, Tyrone D. ; London, Edythe ; Poldrack, Russell A. ; Sabb, Fred W. ; Congdon, Eliza ; Conley, Emily Drabant ; Scult, Matthew A. ; Dickinson, Dwight ; Straub, Richard E. ; Donohoe, Gary ; Morris, Derek ; Corvin, Aiden ; Gill, Michael ; Hariri, Ahmad R. ; Weinberger, Daniel R. ; Pendleton, Neil ; Bitsios, Panos ; Rujescu, Dan ; Lahti, Jari ; Hellard, Stephanie Le ; Keller, Matthew C. ; Andreassen, Ole A. ; Deary, Ian J. ; Glahn, David C. ; Chunyu, Liu ; Malhotra, Anil K. ; Lencz, Todd. / Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. In: Neuropsychopharmacology. 2021.

@article{bb348d3218a1453883b5ea7342e1ee12,

title = "Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics",

abstract = "Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.",

keywords = "LBC1936, heritable quantitative trait",

author = "Max Lam and Chen Chia-Yen and Xia Yan and Hill, {W. David} and Trampush, {Joey W.} and Jin Yu and Emma Knowles and Gail Davies and Eli Stahl and Laura Huckins and Liewald, {David C.} and Srdjan Djurovic and Ingrid Melle and Andrea Christoforou and Ivar Reinvang and Pamela DeRosse and Lundervold, {Astri J.} and Steen, {Vidar M.} and Thomas Espeseth and Katri R{\"a}ikk{\"o}nen and Elisabeth Widen and Aarno Palotie and Eriksson, {Johan G.} and Ina Giegling and Bettina Konte and Hartmann, {Annette M.} and Panos Roussos and Stella Giakoumaki and Burdick, {Katherine E.} and Antony Payton and William Ollier and Ornit Chiba-Falek and Koltai, {Deborah K.} and Need, {Anna C.} and Cirulli, {Elizabeth T.} and Voineskos, {Aristotle N.} and Stefanis, {Nikos C.} and Dimitrios Avramopoulos and Alex Hatzimanolis and Nikolaos Smyrnis and Bilder, {Robert M.} and Freimer, {Nelson A.} and Cannon, {Tyrone D.} and Edythe London and Poldrack, {Russell A.} and Sabb, {Fred W.} and Eliza Congdon and Conley, {Emily Drabant} and Scult, {Matthew A.} and Dwight Dickinson and Straub, {Richard E.} and Gary Donohoe and Derek Morris and Aiden Corvin and Michael Gill and Hariri, {Ahmad R.} and Weinberger, {Daniel R.} and Neil Pendleton and Panos Bitsios and Dan Rujescu and Jari Lahti and Hellard, {Stephanie Le} and Keller, {Matthew C.} and Andreassen, {Ole A.} and Deary, {Ian J.} and Glahn, {David C.} and Liu Chunyu and Malhotra, {Anil K.} and Todd Lencz",

year = "2021",

month = may,

day = "25",

doi = "10.1038/s41386-021-01023-4",

language = "Undefined/Unknown",

journal = "Neuropsychopharmacology",

issn = "0893-133X",

publisher = "Nature Publishing Group",

}

Lam, M, Chia-Yen, C, Yan, X, Hill, WD, Trampush, JW, Yu, J, Knowles, E, Davies, G, Stahl, E, Huckins, L, Liewald, DC, Djurovic, S, Melle, I, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Hartmann, AM, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Chiba-Falek, O, Koltai, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Hellard, SL, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Chunyu, L, Malhotra, AK & Lencz, T 2021, 'Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics', Neuropsychopharmacology. https://doi.org/10.1038/s41386-021-01023-4

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. / Lam, Max; Chia-Yen, Chen; Yan, Xia; Hill, W. David; Trampush, Joey W.; Yu, Jin; Knowles, Emma; Davies, Gail; Stahl, Eli; Huckins, Laura; Liewald, David C.; Djurovic, Srdjan; Melle, Ingrid; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J.; Steen, Vidar M.; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G.; Giegling, Ina; Konte, Bettina; Hartmann, Annette M.; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E.; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Koltai, Deborah K.; Need, Anna C.; Cirulli, Elizabeth T.; Voineskos, Aristotle N.; Stefanis, Nikos C.; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Smyrnis, Nikolaos; Bilder, Robert M.; Freimer, Nelson A.; Cannon, Tyrone D.; London, Edythe; Poldrack, Russell A.; Sabb, Fred W.; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A.; Dickinson, Dwight; Straub, Richard E.; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R.; Weinberger, Daniel R.; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Hellard, Stephanie Le; Keller, Matthew C.; Andreassen, Ole A.; Deary, Ian J.; Glahn, David C.; Chunyu, Liu; Malhotra, Anil K.; Lencz, Todd.

In: Neuropsychopharmacology, 25.05.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

AU - Lam, Max

AU - Chia-Yen, Chen

AU - Yan, Xia

AU - Hill, W. David

AU - Trampush, Joey W.

AU - Yu, Jin

AU - Knowles, Emma

AU - Davies, Gail

AU - Stahl, Eli

AU - Huckins, Laura

AU - Liewald, David C.

AU - Djurovic, Srdjan

AU - Melle, Ingrid

AU - Christoforou, Andrea

AU - Reinvang, Ivar

AU - DeRosse, Pamela

AU - Lundervold, Astri J.

AU - Steen, Vidar M.

AU - Espeseth, Thomas

AU - Räikkönen, Katri

AU - Widen, Elisabeth

AU - Palotie, Aarno

AU - Eriksson, Johan G.

AU - Giegling, Ina

AU - Konte, Bettina

AU - Hartmann, Annette M.

AU - Roussos, Panos

AU - Giakoumaki, Stella

AU - Burdick, Katherine E.

AU - Payton, Antony

AU - Ollier, William

AU - Chiba-Falek, Ornit

AU - Koltai, Deborah K.

AU - Need, Anna C.

AU - Cirulli, Elizabeth T.

AU - Voineskos, Aristotle N.

AU - Stefanis, Nikos C.

AU - Avramopoulos, Dimitrios

AU - Hatzimanolis, Alex

AU - Smyrnis, Nikolaos

AU - Bilder, Robert M.

AU - Freimer, Nelson A.

AU - Cannon, Tyrone D.

AU - London, Edythe

AU - Poldrack, Russell A.

AU - Sabb, Fred W.

AU - Congdon, Eliza

AU - Conley, Emily Drabant

AU - Scult, Matthew A.

AU - Dickinson, Dwight

AU - Straub, Richard E.

AU - Donohoe, Gary

AU - Morris, Derek

AU - Corvin, Aiden

AU - Gill, Michael

AU - Hariri, Ahmad R.

AU - Weinberger, Daniel R.

AU - Pendleton, Neil

AU - Bitsios, Panos

AU - Rujescu, Dan

AU - Lahti, Jari

AU - Hellard, Stephanie Le

AU - Keller, Matthew C.

AU - Andreassen, Ole A.

AU - Deary, Ian J.

AU - Glahn, David C.

AU - Chunyu, Liu

AU - Malhotra, Anil K.

AU - Lencz, Todd

PY - 2021/5/25

Y1 - 2021/5/25

N2 - Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

AB - Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

KW - LBC1936

KW - heritable quantitative trait

U2 - 10.1038/s41386-021-01023-4

DO - 10.1038/s41386-021-01023-4

M3 - Article

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

ER -