Table 3 (following pages). Illustrative examples of mapping SNPs curated in the GWAS catalogue to genomic linkage dis-equilibrium (LD) intervals containing targets of licensed and clinically used drugs (adapted with modification from.Finan C, Gaulton A, et al. Sci. Translational Med. 2017 Mar 29; 9(383). pii: eaag1166. doi: 10.1126/scitranslmed.aag1166).
From: Improving the odds of drug development success through human genomics: modelling study
Gene | Drug | Molecule type | Curation code | GWAS EFO term | Drug Indication (FDB) | Associated Variant | Reference (pmid) | Minimun distance from druggable gene (bp) | Distance rank of druggable gene | Number of Genes In LD interval | Number of Druggable genes in LD interval |
|---|---|---|---|---|---|---|---|---|---|---|---|
ALDH2 | DISULFIRAM | Small molecule | 1 | alcohol drinking|drinking behavior | Alcoholism (adjunctive treatment) | rs11066280| rs12229654| rs2074356|rs671 | 21270382| 21372407| 23364009| 24277619 | 6016–790230 | 1–18 | 22–33 | 2–4 |
PDE4D | AMINOPHYLLINE | Small molecule | 1 | asthma | Acute asthma|Acute exacerbation of chronic obstructive airways disease|Bronchial asthma|Chronic obstructive pulmonary disease|Left ventricular failure - cardiac failure - cardiac asthma|Reversible airways obstruction|Routine maintenance therapy in chronic bronchitis and asthma | rs1588265 | 19426955 | 448153 | 1 | 2 | 1 |
IGF1R | MECASERMIN | Protein | 1 | body height | Growth failure due to primary IGF-1 deficiency | rs2871865 | 20881960| 25429064 | 2696 | 1 | 2 | 1 |
TNFSF11 | DENOSUMAB | Antibody | 1 | bone density | Prevention of skeletal related events in advanced malignancy involving bone|Treatment of bone loss associated with hormone ablation in prostate cancer|Treatment of osteoporosis in postmenopausal women to prevent fractures | rs17536328| rs9525638 | 24945404 | 6157–8295 | 1 | 1 | 1 |
ESR1 | TAMOXIFEN CITRATE | Small molecule | 1 | breast carcinoma | Carcinoma of breast|Infertility - female - anovulatory | rs140068132| rs3757318|rs9383938 | 22976474| 23535729| 25327703 | 9531–63713 | 1–2 | 2 | 1 |
PLG | ALTEPLASE | Enzyme | 1 | coronary heart disease|large artery stroke|stroke | Acute ischaemic stroke: fibrinolytic treatment| Thrombolysis in acute myocardial infarction| Thrombolysis of occluded central venous access devices|Thrombolytic treatment in acute massive pulmonary embolism | rs10455872 | 24262325 | 113152 | 3 | 3 | 2 |
TNF | ADALIMUMAB | Antibody | 1 | Crohn’s disease | Active polyarticular juvenile chronic arthritis-inadequate response to MTX|Active progressive rheumatoid arthritis|Moderate to severe plaque psoriasis: when other treatment is inappropriate|Moderate/severe ulcerative colitis: when other treatment is inappropriate|Rheumatoid arthritis when inadequate response to DMARDs incl. methotrexate|Severe active rheumatoid arthritis|Severe ankylosing spondylitis in adults if conventional therapy inadequate|Treatment of active & progressive psoriatic arthritis when DMARD inadequate|Treatment of active Crohn’s disease | rs1799964 | 21102463 | 1036 | 2 | 13 | 4 |
CACNA1D | AMLODIPINE | Small molecule | 1 | diastolic blood pressure | Essential hypertension when stabilised on same ingreds.in same proportions|Hypertension-not adequately controlled by individual components|Prinzmetal’s angina|Prophylaxis of chronic stable angina pectoris|Treatment of essential hypertension| | rs9810888 | 25249183 | 106912 | 1 | 1 | 1 |
NPC1L1 | EZETIMIBE | Small molecule | 1 | LDL cholesterol|low density lipoprotein cholesterol measurement|total cholesterol measurement | Combined hyperlipidaemia: lipid lowering therapy adjunct to diet|Homozygous familial hypercholesterolaemia (adjunct to statin therapy)|Homozygous familial hypercholesterolaemia: Adjunct to diet|Homozygous sitosterolaemia (phytosterolaemia)|Primary hypercholesterolaemia (hyperlipidaemia type IIa): Adjunct to diet|Primary hypercholesterolaemia: lipid lowering therapy adjunct to diet | rs2072183 | 20686565| 24097068 | 1734 | 1 | 1 | 1 |
PPARA | GEMFIBROZIL | Small molecule | 1 | LDL cholesterol|low density lipoprotein cholesterol measurement|total cholesterol measurement | Mixed hyperlipidaemia when statin is contraindicated or not tolerated|Primary hypercholesterolaemia: lipid lowering therapy adjunct to diet|Reduction of cardiac events in hypercholesterolaemia|Severe hypertriglyceridaemia with or without low HDL cholesterol | rs4253772 | 24097068 | 12050 | 1 | 7 | 2 |
CASR | CINACALCET HYDROCHLORIDE | Small molecule | 1 | calcuim measurment | Homoeopathic|Hypercalcaemia due to malignant disease|Hypercalcaemia in primary HPT when parathyroidectomy contraindicated|Secondary hyperparathyroidism in end stage renal disease: treatment | rs17251221| rs1801725 | 20661308| 20705733| 24068962 | 1585–12095 | 1 | 5 | 1 |
IL6R | TOCILIZUMAB | Antibody | 1 | rheumatoid arthritis | Active juvenile idiopathic arthritis (unresp to NSAIDs) in comb with MTX|Active juvenile idiopathic arthritis when inadequate response to NSAIDs|Rheumatoid arthritis (unresp to DMARD/TNF inhib.) in comb with methotrexate|Rheumatoid arthritis when inadequate response to DMARDs incl. methotrexate | rs2228145 | 24390342 | 14956 | 1 | 1 | 1 |
TNF | ADALIMUMAB | Antibody | 1 | rheumatoid arthritis | Active polyarticular juvenile chronic arthritis-inadequate response to MTX|Active progressive rheumatoid arthritis|Moderate to severe plaque psoriasis: when other treatment is inappropriate|Moderate/severe ulcerative colitis: when other treatment is inappropriate|Rheumatoid arthritis when inadequate response to DMARDs incl. methotrexate|Severe active rheumatoid arthritis|Severe ankylosing spondylitis in adults if conventional therapy inadequate|Treatment of active & progressive psoriatic arthritis when DMARD inadequate|Treatment of active Crohn’s disease | rs2596565 | 24532677 | 190015 | 24 | 145 | 27 |
ABCC8 | GLIPIZIDE | Small molecule | 1 | type II diabetes mellitus | Non insulin dependent diabetes mellitus when diet has failed | rs5219 | 19056611 | 4860–5802 | 3 | 5 | 3 |
ABCC8 | GLYBURIDE | Small molecule | 1 | type II diabetes mellitus | Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone | rs5215|rs5219 | 17463248| 17463249| 19056611| 24509480 | 4860–5802 | 3 | 5 | 3 |
ABCC8 | NATEGLINIDE | Small molecule | 1 | type II diabetes mellitus | Control of type-2 diabetes (NIDDM) with metformin if metformin inadequate | rs5219 | 19056611 | 4860–5802 | 3 | 5 | 3 |
ABCC8 | REPAGLINIDE | Small molecule | 1 | type II diabetes mellitus | Control of type-2 diabetes (NIDDM) with metformin if metformin inadequate|Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone | rs5219 | 19056611 | 4860–5802 | 3 | 5 | 3 |
KCNJ11 | GLIMEPIRIDE | Small molecule | 1 | type II diabetes mellitus | Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone | rs5219 | 19056611 | 1224–1306 | 1 | 5 | 3 |
KCNJ11 | GLIPIZIDE | Small molecule | 1 | type II diabetes mellitus | Non insulin dependent diabetes mellitus when diet has failed | rs5219 | 19056611 | 1224–1306 | 1 | 5 | 3 |
KCNJ11 | GLYBURIDE | Small molecule | 1 | type II diabetes mellitus | Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone | rs5215|rs5219 | 17463248| 17463249| 19056611| 24509480 | 1224–1306 | 1 | 5 | 3 |
KCNJ11 | NATEGLINIDE | Small molecule | 1 | type II diabetes mellitus | Control of type-2 diabetes (NIDDM) with metformin if metformin inadequate | rs5219 | 19056611 | 1224–1306 | 1 | 5 | 3 |
KCNJ11 | REPAGLINIDE | Small molecule | 1 | type II diabetes mellitus | Control of type-2 diabetes (NIDDM) with metformin if metformin inadequate|Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone | rs5219 | 19056611 | 1224–1306 | 1 | 5 | 3 |
PPARG | PIOGLITAZONE HYDROCHLORIDE | Small molecule | 1 | type II diabetes mellitus | Combination treatment of Type 2 diabetes with insulin|Control of type-2 diabetes if metformin+sulphonylurea therapy is inadequate|Monotherapy for type2 diabetes if overweight and metformin inappropriate|Oral combination treatment of type 2 diabetes | rs1801282 | 24509480 | 64258 | 1 | 1 | 1 |
SCN1A | OXCARBAZEPINE | Small molecule | 1 | Mesial temporal lobe epilepsy with hippocampal sclerosis|febrile seizures | Epilepsy - combination of both partial and tonic-clonic seizures|Epilepsy - partial seizures | rs7587026 | 24014518 | 5773–52194 | 1 | 3 | 1 |
GRIN3B | MEMANTINE HYDROCHLORIDE | Small molecule | 1 | Alzheimers disease | Moderate to severe Alzheimer’s disease|No information available | rs115550680 | 23571587 | 40689 | 8 | 8 | 2 |
SLC22A12 | SULFINPYRAZONE | Small molecule | 1 | urate measurement | Gout (prophylaxis)|Gouty arthritis|Hyperuricaemia | rs2078267|rs478607 | 20884846| 23263486 | 23999–108243 | 2–3 | 2–3 | 2 |
SLC22A11 | PROBENECID | Small molecule | 1 | urate measurement|uric acid measurement | rs17300741|rs2078267 | 19503597| 20884846| 23263486 | 6233–8364 | 1 | 1–2 | 1–2 | |
SCN2A | CARBAMAZEPINE | Small molecule | 2 | febrile seizures | Epilepsy - grand mal|Epilepsy - partial seizures|Epilepsy - tonic-clonic seizures|Prophylaxis of manic-depressive illness unresponsive to lithium|Trigeminal neuralgia | rs3769955 | 25344690 | 14186 | 1 | 1 | 1 |
DIO1 | PROPYLTHIOURACIL | Small molecule | 3 | thyroxine|thyroxine measurement | Hyperthyroidism|Thyrotoxic crisis|Unlicensed product | rs2235544 | 23408906 | 1189 | 1 | 4 | 1 |
PDE4D | DIPYRIDAMOLE | Small molecule | 4 | asthma | Alternative to exercise stress in thallium-201 myocardial imaging|Ischemic stroke: Secondary prevention (with/without aspirin)|Secondary prevention of ischaemic stroke|Secondary prevention of transient ischaemic attacks|Thromboembolism+prosthetic heart valve: prophylaxis (+oral anticoagulant)|Transient ischemic attacks: Secondary prevention (with/without aspirin) | rs1588265 | 19426955 | 448153 | 1 | 2 | 1 |
ACHE | RIVASTIGMINE | Small molecule | 4 | resting heart rate | Mild - moderate dementia in Alzheimer’s disease|Mild - moderate dementia in idiopathic Parkinson’s disease | rs12666989|rs314370 | 20639392 | 861–34407 | 3–7 | 9 | 4 |
ACHE | NEOSTIGMINE METHYLSULFATE | Small molecule | 4 | heart rate | Myasthenia gravis|Paralytic ileus|Paroxysmal supra-ventricular tachyarrhythmias|Post operative distention| Post operative urinary retention|Reversal of residual competitive neuromuscular block|Unlicensed product | rs13245899 | 23583979 | 861–34407 | 1–7l | 9 | 4 |
CHRM2 | TOLTERODINE TARTRATE | Small molecule | 4 | heart rate | Symptomatic treatment of urinary urgency, frequency or urge incontinence | rs2350782 | 23583979 | 62368 | 1 | 3 | 1 |
