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Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

ABSTRACT: Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

SUBMITTER: Lam M

PROVIDER: S-EPMC5789458 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Lam Max M Trampush Joey W JW Yu Jin J Knowles Emma E Davies Gail G Liewald David C DC Starr John M JM Djurovic Srdjan S Melle Ingrid I Sundet Kjetil K Christoforou Andrea A Reinvang Ivar I DeRosse Pamela P Lundervold Astri J AJ Steen Vidar M VM Espeseth Thomas T Räikkönen Katri K Widen Elisabeth E Palotie Aarno A Eriksson Johan G JG Giegling Ina I Konte Bettina B Roussos Panos P Giakoumaki Stella S Burdick Katherine E KE Payton Antony A Ollier William W Chiba-Falek Ornit O Attix Deborah K DK Need Anna C AC Cirulli Elizabeth T ET Voineskos Aristotle N AN Stefanis Nikos C NC Avramopoulos Dimitrios D Hatzimanolis Alex A Arking Dan E DE Smyrnis Nikolaos N Bilder Robert M RM Freimer Nelson A NA Cannon Tyrone D TD London Edythe E Poldrack Russell A RA Sabb Fred W FW Congdon Eliza E Conley Emily Drabant ED Scult Matthew A MA Dickinson Dwight D Straub Richard E RE Donohoe Gary G Morris Derek D Corvin Aiden A Gill Michael M Hariri Ahmad R AR Weinberger Daniel R DR Pendleton Neil N Bitsios Panos P Rujescu Dan D Lahti Jari J Le Hellard Stephanie S Keller Matthew C MC Andreassen Ole A OA Deary Ian J IJ Glahn David C DC Malhotra Anil K AK Lencz Todd T

Cell reports 20171101 9

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic r ...[more]

PMID: 29186694

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Project description:BackgroundPromiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.MethodsWe perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.ResultsWe observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.ConclusionsThe detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.

Dataset Information

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Publications

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

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