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

Max Lam^{1

2

3

4

5}, Chia-Yen Chen^{3

6

7}, Tian Ge^{2

7}, Yan Xia^{8

9}, David W Hill^{10

11}, Joey W Trampush¹², Jin Yu¹, Emma Knowles^{13

14

15}, Gail Davies^{10

11}, Eli A Stahl^{16

17

18}, Laura Huckins^{17

18}, David C Liewald¹¹, Srdjan Djurovic^{19

20}, Ingrid Melle²¹, Andrea Christoforou^{22

23}, Ivar Reinvang²⁴, Pamela DeRosse^{1

4

25}, Astri J Lundervold²⁶, Vidar M Steen^{20

23}, Thomas Espeseth^{21

24}, Katri Räikkönen²⁷, Elisabeth Widen²⁸, Aarno Palotie^{28

29

30}, Johan G Eriksson^{31

32

33}, Ina Giegling³⁴, Bettina Konte³⁴, Annette M Hartmann³⁴, Panos Roussos^{17

18

35}, Stella Giakoumaki³⁶, Katherine E Burdick^{17

35

37}, Antony Payton³⁸, William Ollier^{39

40}, Ornit Chiba-Falek⁴¹, Deborah C Koltai⁴², Anna C Need⁴³, Elizabeth T Cirulli⁴⁴, Aristotle N Voineskos⁴⁵, Nikos C Stefanis^{46

47

48}, Dimitrios Avramopoulos^{49

50}, Alex Hatzimanolis^{46

47

48}, Nikolaos Smyrnis^{46

47}, Robert M Bilder⁵¹, Nelson B Freimer⁵¹, Tyrone D Cannon^{52

53}, Edythe London⁵¹, Russell A Poldrack⁵⁴, Fred W Sabb⁵⁵, Eliza Congdon⁵¹, Emily Drabant Conley⁵⁶, Matthew A Scult^{57

58}, Dwight Dickinson⁵⁹, Richard E Straub⁶⁰, Gary Donohoe⁶¹, Derek Morris⁶¹, Aiden Corvin⁶², Michael Gill⁶², Ahmad R Hariri⁵⁸, Daniel R Weinberger⁶⁰, Neil Pendleton⁶³, Panos Bitsios⁶⁴, Dan Rujescu³⁴, Jari Lahti^{27

65}, Stephanie Le Hellard^{20

23}, Matthew C Keller⁶⁶, Ole A Andreassen^{21

67}, Ian J Deary^{10

11}, David C Glahn^{13

14

15}, Hailiang Huang^{2

3}, Chunyu Liu^{8

9}, Anil K Malhotra^{1

4

25}, Todd Lencz^{68

69

70}

Affiliations

¹ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴ Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
⁵ Institute of Mental Health, Singapore, Singapore.
⁶ Biogen, Inc, Cambridge, MA, USA.
⁷ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁸ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
⁹ Psychiatry Department, SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁰ Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland, UK.
¹¹ Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹² Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA, USA.
¹⁴ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁵ Olin Neuropsychic Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
¹⁶ Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
¹⁷ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁰ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
²¹ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²² Spaulding Rehabilitation Hospital Boston, Charlestown, MA, USA.
²³ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
²⁴ Department of Psychology, University of Oslo, Oslo, Norway.
²⁵ Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁶ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
²⁷ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁸ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
²⁹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
³⁰ Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
³¹ Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³² Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³³ Folkhälsan Research Center, Helsinki, Finland.
³⁴ Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
³⁵ Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA.
³⁶ Department of Psychology, University of Crete, Crete, Greece.
³⁷ Department of Psychiatry - Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁸ Division of Informatics, Imaging & Data Sciences, School of Health Sciences, The University of Manchester, Manchester, UK.
³⁹ Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK.
⁴⁰ School of Healthcare Sciences, Manchester Metropolitan University, Manchester, United Kingdom.
⁴¹ Division of Translational Brain Sciences, Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
⁴² Psychiatry and Behavioral Sciences, Division of Medical Psychology, and Department of Neurology, Duke University Medical Center, Durham, NC, USA.
⁴³ William Harvey Research Institute, Queen Mary University of London, London, UK.
⁴⁴ Helix Inc., San Diego, CA, USA.
⁴⁵ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
⁴⁶ 2nd Department of Psychiatry, National and Kapodistrian University of Athens Medical School, University General Hospital "ATTIKON", Athens, Greece.
⁴⁷ University Mental Health Research Institute, Athens, Greece.
⁴⁸ Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
⁴⁹ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁰ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵¹ UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
⁵² Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵³ Department of Psychology, Yale University, New Haven, CT, USA.
⁵⁴ Department of Psychology, Stanford University, Palo Alto, CA, USA.
⁵⁵ Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
⁵⁶ 23andMe, Inc., Mountain View, CA, USA.
⁵⁷ Weill Cornell Psychiatry at NewYork-Presbyterian, Weill Cornell Medical Center, New York, NY, USA.
⁵⁸ Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA.
⁵⁹ Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.
⁶⁰ Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
⁶¹ Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
⁶² Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁶³ Division of Neuroscience and Experimental Psychology/School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.
⁶⁴ Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, GR, Greece.
⁶⁵ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
⁶⁶ Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
⁶⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶⁸ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA. tlencz@northwell.edu.
⁶⁹ Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA. tlencz@northwell.edu.
⁷⁰ Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. tlencz@northwell.edu.

PMID: 34035472
PMCID: PMC8357785
DOI: 10.1038/s41386-021-01023-4

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

Max Lam et al. Neuropsychopharmacology. 2021 Sep.

. 2021 Sep;46(10):1788-1801.

doi: 10.1038/s41386-021-01023-4. Epub 2021 May 25.

Authors

Affiliations

¹ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴ Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
⁵ Institute of Mental Health, Singapore, Singapore.
⁶ Biogen, Inc, Cambridge, MA, USA.
⁷ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁸ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
⁹ Psychiatry Department, SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁰ Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland, UK.
¹¹ Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹² Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, MA, USA.
¹⁴ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁵ Olin Neuropsychic Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
¹⁶ Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
¹⁷ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁰ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
²¹ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²² Spaulding Rehabilitation Hospital Boston, Charlestown, MA, USA.
²³ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
²⁴ Department of Psychology, University of Oslo, Oslo, Norway.
²⁵ Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁶ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
²⁷ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁸ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
²⁹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
³⁰ Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
³¹ Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³² Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³³ Folkhälsan Research Center, Helsinki, Finland.
³⁴ Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany.
³⁵ Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA.
³⁶ Department of Psychology, University of Crete, Crete, Greece.
³⁷ Department of Psychiatry - Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁸ Division of Informatics, Imaging & Data Sciences, School of Health Sciences, The University of Manchester, Manchester, UK.
³⁹ Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK.
⁴⁰ School of Healthcare Sciences, Manchester Metropolitan University, Manchester, United Kingdom.
⁴¹ Division of Translational Brain Sciences, Department of Neurology, Bryan Alzheimer's Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA.
⁴² Psychiatry and Behavioral Sciences, Division of Medical Psychology, and Department of Neurology, Duke University Medical Center, Durham, NC, USA.
⁴³ William Harvey Research Institute, Queen Mary University of London, London, UK.
⁴⁴ Helix Inc., San Diego, CA, USA.
⁴⁵ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
⁴⁶ 2nd Department of Psychiatry, National and Kapodistrian University of Athens Medical School, University General Hospital "ATTIKON", Athens, Greece.
⁴⁷ University Mental Health Research Institute, Athens, Greece.
⁴⁸ Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
⁴⁹ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁰ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵¹ UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
⁵² Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵³ Department of Psychology, Yale University, New Haven, CT, USA.
⁵⁴ Department of Psychology, Stanford University, Palo Alto, CA, USA.
⁵⁵ Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA.
⁵⁶ 23andMe, Inc., Mountain View, CA, USA.
⁵⁷ Weill Cornell Psychiatry at NewYork-Presbyterian, Weill Cornell Medical Center, New York, NY, USA.
⁵⁸ Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA.
⁵⁹ Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.
⁶⁰ Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.
⁶¹ Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
⁶² Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁶³ Division of Neuroscience and Experimental Psychology/School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.
⁶⁴ Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, GR, Greece.
⁶⁵ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
⁶⁶ Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
⁶⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶⁸ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA. tlencz@northwell.edu.
⁶⁹ Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA. tlencz@northwell.edu.
⁷⁰ Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. tlencz@northwell.edu.

PMID: 34035472
PMCID: PMC8357785
DOI: 10.1038/s41386-021-01023-4

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.

PubMed Disclaimer

Figures

**Fig. 1. Workflow for the present study.**
The overall data analytic strategy follows a broad strategy of (i) locus discovery, (ii) gene-based characterization, and (iii) gene-to-drug annotations. The green box at top summarizes locus discovery procedures and characterization of results. Yellow box summarizes downstream analysis of summary statistics, resulting in a set of genes available for druggability analysis displayed at figure bottom (red brackets). At each step, location of further details in Tables, Figures, and Supplementary Materials is specified. SMR summary statistics mendelian randomization, FUMA functional mapping and annotation of GWAS, eQTL expression quantitative trait locus, rQTL ribosomal occupancy qtl, sQTL splicing qtl, evQTL expression variation qtl.

**Fig. 2. GWAS association plots for Cognitive MTAG.**
A QQ-plot. B SNP annotation plot. C Manhattan plot for General Cognitive Ability. D Venn Diagram showing loci overlap for input GWAS and MTAG results. E MAGMA gene property analysis for overall GTEXv7. F MAGMA gene property analysis using BrainSpan.

**Fig. 3. Venn diagram of “High Confidence” genes and gene identification approaches.**
Genes highlighted in blue were deemed as most likely having gene targets that were suitable for nootropic re-purposing.

See this image and copyright information in PMC

References

1. King EA, Davis JW, Degner JF. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 2019;15:e1008489. doi: 10.1371/journal.pgen.1008489. - DOI - PMC - PubMed
1. So H-C, Chau CK-L, Chiu W-T, Ho K-S, Lo C-P, Yim SH-Y, et al. Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry. Nat Neurosci. 2017;20:1342–9. doi: 10.1038/nn.4618. - DOI - PubMed
1. Breen G, Li Q, Roth BL, O’Donnell P, Didriksen M, Dolmetsch R, et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci. 2016;19:1392–6. doi: 10.1038/nn.4411. - DOI - PMC - PubMed
1. Lencz T, Malhotra AK. Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic. Mol Psychiatry. 2015;20:820–6. doi: 10.1038/mp.2015.28. - DOI - PMC - PubMed
1. Green MJ, Girshkin L, Kremerskothen K, Watkeys O, Quidé Y. A systematic review of studies reporting data-driven cognitive subtypes across the psychosis spectrum. Neuropsychol Rev. 2019. 10.1007/s11065-019-09422-7. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical