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

Lam, M ORCID: https://orcid.org/0000-0002-4256-7844, Chen, CY, Ge, T, Xia, Y, Hill, DW, Trampush, JW, Yu, J, Knowles, E, Davies, G ORCID: https://orcid.org/0000-0003-1120-7026, Stahl, EA, Huckins, L, Liewald, DC ORCID: https://orcid.org/0000-0002-0544-7368, Djurovic, S, Melle, I ORCID: https://orcid.org/0000-0002-9783-548X, Christoforou, A, Reinvang, I, DeRosse, P ORCID: https://orcid.org/0000-0003-0823-8163, Lundervold, AJ ORCID: https://orcid.org/0000-0002-6819-6164, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B ORCID: https://orcid.org/0000-0001-5287-308X, Hartmann, AM, Roussos, P ORCID: https://orcid.org/0000-0002-4640-6239, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W ORCID: https://orcid.org/0000-0001-6502-6584, Chiba-Falek, O ORCID: https://orcid.org/0000-0002-2529-8785, Koltai, DC, Need, AC, Cirulli, ET, Voineskos, AN ORCID: https://orcid.org/0000-0003-0156-0395, Stefanis, NC, Avramopoulos, D ORCID: https://orcid.org/0000-0003-1492-9104, Hatzimanolis, A, Smyrnis, N, Bilder, RM ORCID: https://orcid.org/0000-0001-5085-7852, Freimer, NB, Cannon, TD, London, E ORCID: https://orcid.org/0000-0003-3577-7808, Poldrack, RA ORCID: https://orcid.org/0000-0001-6755-0259, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D ORCID: https://orcid.org/0000-0002-3413-570X, Corvin, A, Gill, M ORCID: https://orcid.org/0000-0003-0206-5337, Hariri, AR, Weinberger, DR ORCID: https://orcid.org/0000-0003-2409-2969, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J ORCID: https://orcid.org/0000-0002-4310-5297, Le Hellard, S, Keller, MC, Andreassen, OA ORCID: https://orcid.org/0000-0002-4461-3568, Deary, IJ ORCID: https://orcid.org/0000-0002-1733-263X, Glahn, DC, Huang, H, Liu, C ORCID: https://orcid.org/0000-0002-5986-4415, Malhotra, AK and Lencz, T ORCID: https://orcid.org/0000-0001-8586-338X (2021) Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Neuropsychopharmacology, 46 (10). pp. 1788-1801. ISSN 0893-133X

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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.