Table 2.

Prioritized genes for nootropic re-purposing.

Gene ID	Gene name	Predicted nootropic function	Drug name(s)	MOA	Drug indications
CA1	Carbonic anhydrase 1	Antagonist	Acetazolamide Benzthiazide Brinzolamide Chlorthalidone Diclofenamide Dorzolamide Ethoxzolamide Methazolamide Topiramate Trichlormethiazide Methyclothiazide Levosulpiride Zonisamide Bendroflumethiazide Hydroflumethiazide Coumarin Amlodipine	• Carbonic anhydrase inhibitor • Glutamate receptor antagonist • Kainate receptor antagonist • Chloride channel blocker • Chloride reabsorption inhibitor • Dopamine receptor antagonist • Sodium channel blocker • T-type calcium channel blocker • Sodium/potassium/chloride transporter inhibitor • Vitamin K antagonist • Calcium channel blocker	Congestive heart failure Duodenal ulcer disease Dyspepsia Edema Epilepsy Glaucoma Hypertension Migraine headache Ocular hypertension Acute glomerulonephritis (AGN) Anxiety Asthma Celiac disease Chronic renal failure Chronic stable angina Coronary artery disease (CAD) Hepatic cirrhosis Irritable bowel syndrome Nephrotic syndrome Premature ejaculation (PE) Psychosis Schizophrenia Seizures Ulcerative colitis Vertigo
CA13	Carbonic anhydrase 13	Antagonist	Ethoxzolamide Zonisamide	• Carbonic anhydrase inhibitor • Sodium channel blocker • T-type calcium channel blocker	Glaucoma Duodenal ulcer disease Epilepsy
CACNA2D2	Calcium voltage-gated channel auxiliary subunit alpha2delta 2	Agonist	Gabapentin-Enacarbil	Adrenergic receptor agonist	Restless leg syndrome Postherpetic neuralgia
CACNG3	Calcium voltage-gated channel auxiliary subunit gamma3	Agonist	Gabapentin-enacarbil	Adrenergic receptor agonist	Restless leg syndrome Postherpetic neuralgia
CLCN2	Chloride voltage-gated channel 2	Agonist	Lubiprostone	Chloride channel activator	Constipation Irritable bowel syndrome
DHODH	Dihydroorotate dehydrogenase (quinone)	Antagonist	Leflunomide Atovaquone Teriflunomide	• Dihydroorotate dehydrogenase inhibitor • Mitochondrial electron transport inhibitor • PDGFR tyrosine kinase receptor inhibitor	Multiple Sclerosis Rheumatoid Arthritis Pneumonia

DPP4	Dipeptidyl peptidase 4	Antagonist	Alogliptin Anagliptin Linagliptin Saxagliptin Sitagliptin Teneligliptin Trelagliptin Vildagliptin Atorvastatin	• Dipeptidyl peptidase inhibitor • HMGCR inhibitor	Diabetes mellitus stroke Cholesterol reduction
GRIA4	Glutamate ionotropic receptor AMPA type subunit 4	Agonist	Piracetam	Acetylcholine agonist	Senile dementia
GRIN2A	Glutamate ionotropic receptor NMDA type subunit 2 A	Antagonist	Acamprosate Amantadine Telbamate Halothane Memantine Atomoxetine Milnacipran Gabapentin	• Glutamate receptor antagonist • Norepinephrine transporter inhibitor • Serotonin-norepinephrine reuptake inhibitor (SNRI) • Calcium channel blocker	Abstinence from alcohol Alzheimer’s disease Epilepsy General anaesthetic Influenza A virus infection Parkinson’s Disease Restless leg syndrome Senile dementia Virus herpes simplex (HSV) Attention deficit/hyperactivity disorder (ADHD) Fibromyalgia Seizures Pain from shingles
HTR1D	5-hydroxytryptamine receptor 1D	Agonist	Serotonin Almotriptan Dihydroergotamine Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan Aripiprazole Oxymetazoline Bromocriptine Cabergoline lIsuride Pramipexole Ropinirole	• Serotonin receptor agonist • Adrenergic receptor agonist • Dopamine receptor agonist • Growth factor receptor activator	Bipolar disorder Depression Migraine headache Schizophrenia Sleeplessness Acromegaly Hyperprolactinemia Nasal congestion Parkinson’s Disease Restless leg syndrome

HTR5A	5-hydroxytryptamine receptor 5 A	Antagonist	Ergotamine Yohimbine Asenapine Clozapine Loxapine Olanzapine Vortioxetine Ketanserin Methysergide	• Serotonin receptor antagonist • Adrenergic receptor antagonist • Dopamine receptor antagonist • Serotonin receptor agonist^	Bipolar disorder Bradycardia Cardiac arrythmia Depression Headache Hypertension Migraine headache Schizophrenia
SLC6A4	Solute carrier family 6 member 4	Agonist	Vortioxetine Dopamine Dextromethorphan Tapentadol	• Serotonin receptor agonist • Dopamine receptor agonist • Glutamate receptor antagonist • Opioid receptor agonist • Sigma receptor agonist	Depression Acute pain Cough suppressant Headache Muscle pain Tremors Ventricular arrhythmias
PDE4C	Phosphodiesterase 4 C	Agonist	Ketotifen	• Phosphodiesterase inhibitor • Histamine receptor agonist • Leukotriene receptor antagonist	Itching
PDE4D	Phosphodiesterase 4D	Antagonist	Aminophylline Doxofylline Caffeine Dyphyllin Ketotifen Ibudilast Apremilast Dipyridamole Pentoxifylline Roflumilast Iloprost	• Phosphodiesterase inhibitor • Adenosine receptor antagonist • Histamine receptor agonist • Leukotriene receptor antagonist • Platelet aggregation inhibitor • Prostanoid receptor agonist	Asthma Bronchitis Chronic obstructive pulmonary disease Claudication Coronary artery disease (CAD) Drowsiness Emphysema Fatigue Hypertension Itching Peripheral artery disease (PAD) Psoriasis Psoriatic arthritis Pulmonary arterial hypertension (PAH) Stroke
PSMA5	Proteasome subunit alpha 5	Antagonist	Bortezomib Carfilzomib	• Proteasome inhibitor • NFkB pathway inhibitor	Multiple myeloma Mantle cell lymphoma (MCL)
THRB	Thyroid hormone receptor beta	Agonist	Levothyroxine Liothyronine Tiratricol	• Thyroid hormone receptor beta	Myxedema coma Hypothyroidism Refetoff syndrome

Predicted nootropic function was obtained from gene expression association with general cognitive ability. MOA, drug names and drug indications were annotated via Broad Institute Connectivity MAP: Drug Re-Purposing hub. Labels in bold directly implicate the gene, while labels in italics indicate drugs and MOA that are consistent with the predicted nootropic function, but only indirectly implicate the gene.

MOA Mechanism of Action.