Scannell, J. W., Blanckley, A., Boldon, H. & Warrington, B.
Diagnosing the decline in pharmaceutical R&D efficiency. Nature Rev. Drug Discov.
11, 191–200 (2012).
Kola, I. & Landis, J.
Can the pharmaceutical industry reduce attrition rates?
Nature Rev. Drug Discov.
3, 711–715 (2004).
Paul, S. M.
et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Rev. Drug Discov.
9, 203–214 (2010). This article provides a good perspective on the challenges facing the pharmaceutical industry, including the need for better preclinical models to validate drug targets.
Trial watch: phase II failures: 2008–2010. Nature Rev. Drug Discov.
10, 328–329 (2011).
DiMasi, J. A. & Faden, L. B.
Competitiveness in follow-on drug R&D: a race or imitation?
Nature Rev. Drug Discov.
10, 23–27 (2011).
Assessing the translatability of drug projects: what needs to be scored to predict success?
Nature Rev. Drug Discov.
8, 541–546 (2009).
The discovery and early use of cortisone. J. R. Soc. Med.
91, 513–517 (1998).
Tobert, J. A.
Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nature Rev. Drug Discov.
2, 517–526 (2003).
Brown, M. S. & Goldstein, J. L.
Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science
185, 61–63 (1974).
Rader, D. J., Cohen, J. & Hobbs, H. H.
Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J. Clin. Invest.
111, 1795–1803 (2003).
The Lovastatin Study Group II. Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia. A multicenter study. JAMA
256, 2829–2834 (1986).
et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genet.
34, 154–156 (2003). This is the first study to describe a gain-of-function mutation in PCSK9 that causes hypercholesterolaemia.
et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genet.
37, 161–165 (2005).
Kotowski, I. K.
et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet.
78, 410–422 (2006).
Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H.
Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med.
354, 1264–1272 (2006). This is a landmark study that relates loss-of-function mutations in PCSK9 to low LDL cholesterol levels and protection from heart disease.
Park, S. W., Moon, Y. A. & Horton, J. D.
Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem.
279, 50630–50638 (2004).
Maxwell, K. N. & Breslow, J. L.
Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl Acad. Sci. USA
101, 7100–7105 (2004).
Stein, E. A.
et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet
380, 29–36 (2012).
Stein, E. A.
et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med.
366, 1108–1118 (2012). This paper describes one of the first clinical trials demonstrating that a drug that mimics the effect of PCSK9 mutations is effective at lowering LDL cholesterol levels in patients.
Cholesterol-lowering blockbuster candidates speed into Phase III trials. Nature Rev. Drug Discov.
11, 817–819 (2012).
et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature Genet.
40, 189–197 (2008).
Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol?: insights from human genetics and clinical trials. J. Am. Coll. Cardiol.
60, 2049–2052 (2012).
Barter, P. & Rye, K. A.
Cholesteryl ester transfer protein inhibition to reduce cardiovascular risk: where are we now?
Trends Pharmacol. Sci.
32, 694–699 (2011).
Bots, M. L.
et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet
370, 153–160 (2007).
Voight, B. F.
et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet
380, 572–580 (2012). This study is an example of how human genetics can be used to deprioritize therapeutic targets, arguing that drugs that raise HDL cholesterol levels will not be effective at lowering the risk of cardiovascular disease.
Mickle, J. E. & Cutting, G. R.
Clinical implications of cystic fibrosis transmembrane conductance regulator mutations. Clin. Chest Med.
19, 443–458 (1998).
et al. Identification of the cystic fibrosis gene: genetic analysis. Science
245, 1073–1080 (1989).
et al. An overview of international literature from cystic fibrosis registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, pregnancy, clinical complications, lung transplantation, and miscellanea. J. Cyst. Fibros.
10, 71–85 (2011).
Ramsey, B. W.
et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med.
365, 1663–1672 (2011). This paper describes clinical trial data for ivacaftor, a drug that has been developed to increase CFTR potentiation and treat patients with cystic fibrosis.
Cox, J. J.
et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature
444, 894–898 (2006).
et al. Mutations in SCN9A, encoding a sodium channel α subunit, in patients with primary erythermalgia. J. Med. Genet.
41, 171–174 (2004).
Drenth, J. P.
et al. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J. Invest. Dermatol.
124, 1333–1338 (2005).
Fertleman, C. R.
et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron
52, 767–774 (2006).
et al. NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci.
28, 11079–11088 (2008).
Drenth, J. P. & Waxman, S. G.
Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clin. Invest.
117, 3603–3609 (2007).
Schmalhofer, W. A.
et al. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol. Pharmacol.
74, 1476–1484 (2008).
et al. Selective silencing of NaV1.7 decreases excitability and conduction in vagal sensory neurons. J. Physiol.
589, 5663–5676 (2011).
Notarangelo, L. D.
et al. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum. Mutat.
18, 255–263 (2001).
van Vollenhoven, R. F.
et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med.
367, 508–519 (2012).
et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med.
367, 495–507 (2012).
Neptune, E. R.
et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet.
33, 407–411 (2003).
Stranger, B. E., Stahl, E. A. & Raj, T.
Progress and promise of genome-wide association studies for human complex trait genetics. Genetics
187, 367–383 (2011).
et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature
491, 119–124 (2012).
et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nature Genet.
40, 1216–1223 (2008).
Fairfax, B. P.
et al. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nature Genet.
44, 502–510 (2012).
Rivas, M. A.
et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nature Genet.
43, 1066–1073 (2011).
Todd, J. A.
Etiology of type 1 diabetes. Immunity
32, 457–467 (2010).
Plenge, R. M.
et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet.
77, 1044–1060 (2005).
et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genet.
44, 1336–1340 (2012).
et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc. Natl Acad. Sci. USA
105, 11869–11874 (2008).
et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc. Natl Acad. Sci. USA
105, 1620–1625 (2008).
et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nature Genet.
39, 1197–1199 (2007).
et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature
423, 293–298 (2003).
Worman, H. J., Fong, L. G., Muchir, A. & Young, S. G.
Laminopathies and the long strange trip from basic cell biology to therapy. J. Clin. Invest.
119, 1825–1836 (2009).
De Sandre-Giovannoli, A.
et al. Lamin A truncation in Hutchinson-Gilford progeria. Science
300, 2055 (2003).
et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann. Hum. Genet.
76, 387–401 (2012).
Imperato-McGinley, J., Guerrero, L., Gautier, T. & Peterson, R. E.
Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science
186, 1213–1215 (1974).
Andersson, S., Berman, D. M., Jenkins, E. P. & Russell, D. W.
Deletion of steroid 5 α-reductase 2 gene in male pseudohermaphroditism. Nature
354, 159–161 (1991).
Rittmaster, R. S.
Finasteride. N. Engl. J. Med.
330, 120–125 (1994).
et al. Use of genome-wide association studies for drug repositioning. Nature Biotech.
30, 317–320 (2012). This is a study that integrated GWAS data with drug databases, thereby showing that the genes targeted by many approved therapies have been implicated by human genetics.
et al. Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. Arterioscler. Thromb. Vasc. Biol.
28, 2078–2084 (2008).
et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet.
26, 76–80 (2000).
Tsoi, L. C.
et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nature Genet.
44, 1341–1348 (2012).
et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genet.
44, 491–501 (2012).
Brooke, B. S.
et al. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N. Engl. J. Med.
358, 2787–2795 (2008).
Klein, R. J.
et al. Complement factor H polymorphism in age-related macular degeneration. Science
308, 385–389 (2005). This study represents one of the first GWASs. Based on findings from this and other studies, drugs targeting the complement pathway are under development for AMD.
et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature Genet.
38, 1055–1059 (2006).
Maller, J. B.
et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nature Genet.
39, 1200–1201 (2007).
et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nature Genet.
43, 1232–1236 (2011).
et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med.
350, 552–559 (2004).
Troutbeck, R., Al-Qureshi, S. & Guymer, R. H.
Therapeutic targeting of the complement system in age-related macular degeneration: a review. Clin. Experiment. Ophthalmol.
40, 18–26 (2012).
Katschke, K. J. Jr
et al. Inhibiting alternative pathway complement activation by targeting the factor D exosite. J. Biol. Chem.
287, 12886–12892 (2012).
Hingorani, A. D. & Casas, J. P.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet
379, 1214–1224 (2012).
Park, H., Bourla, A. B., Kastner, D. L., Colbert, R. A. & Siegel, R. M.
Lighting the fires within: the cell biology of autoinflammatory diseases. Nature Rev. Immunol.
12, 570–580 (2012).
Lunn, M. R. & Stockwell, B. R.
Chemical genetics and orphan genetic diseases. Chem. Biol.
12, 1063–1073 (2005).
Russman, B. S., Iannaccone, S. T. & Samaha, F. J.
A phase 1 trial of riluzole in spinal muscular atrophy. Arch. Neurol.
60, 1601–1603 (2003).
et al. Riluzole pharmacokinetics in young patients with spinal muscular atrophy. Br. J. Clin. Pharmacol.
71, 403–410 (2011).
Wadman, R. I.
et al. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst. Rev.
4, CD006281 (2012).
Dietz, H. C.
New therapeutic approaches to Mendelian disorders. N. Engl. J. Med.
363, 852–863 (2010). This is a good review on therapeutic approaches based on genetic findings from Mendelian diseases, including the example of Marfan's syndrome.
Lorson, C. L., Rindt, H. & Shababi, M.
Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum. Mol. Genet.
19, R111–R118 (2010).
et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science
264, 1474–1477 (1994).
et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell
80, 155–165 (1995).
Hirschhorn, J. N. & Daly, M. J.
Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet.
6, 95–108 (2005).
McCarthy, M. I.
et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet.
9, 356–369 (2008).
Cirulli, E. T. & Goldstein, D. B.
Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature Rev. Genet.
11, 415–425 (2010).
Lander, E. & Kruglyak, L.
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet.
11, 241–247 (1995).
MacArthur, D. G.
et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science
335, 823–828 (2012).
Adzhubei, I. A.
et al. A method and server for predicting damaging missense mutations. Nature Methods
7, 248–249 (2010).
Kumar, P., Henikoff, S. & Ng, P. C.
Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature Protoc.
4, 1073–1081 (2009).
et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature
488, 96–99 (2012). This study shows that a loss-of-function mutation in the APP gene protects against Alzheimer's disease.
et al. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol. Aging
34, 1518.e1–1518.e3 (2013).
Gashaw, I., Ellinghaus, P., Sommer, A. & Asadullah, K.
What makes a good drug target?
Drug Discov. Today
16, 1037–1043 (2011).
Katan, M. B.
Commentary: Mendelian randomization, 18 years on. Int. J. Epidemiol.
33, 10–11 (2004).
Ebrahim, S. & Davey Smith, G.
Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?
123, 15–33 (2008).
et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genet.
41, 56–65 (2009).
Swinney, D. C.
Phenotypic versus target-based drug discovery for first-in-class medicines. Clin. Pharmacol. Ther.
93, 299–301 (2013).
Rossin, E. J.
et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet.
7, e1001273 (2011).
et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genet.
45, 124–130 (2013).
Barabasi, A. L., Gulbahce, N. & Loscalzo, J.
Network medicine: a network-based approach to human disease. Nature Rev. Genet.
12, 56–68 (2011).
Schadt, E. E., Friend, S. H. & Shaywitz, D. A.
A network view of disease and compound screening. Nature Rev. Drug Discov.
8, 286–295 (2009).
Stahl, E. A.
et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nature Genet.
44, 483–489 (2012).
Dietz, H. C.
et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature
352, 337–339 (1991).
International HapMap Consortium. A haplotype map of the human genome. Nature
437, 1299–1320 (2005).
Altshuler, D., Daly, M. J. & Lander, E. S.
Genetic mapping in human disease. Science
322, 881–888 (2008).
Hindorff, L. A.
et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA
106, 9362–9367 (2009).
Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J.
Five years of GWAS discovery. Am. J. Hum. Genet.
90, 7–24 (2012).
Nicolae, D. L.
et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet.
6, e1000888 (2010).
et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet.
5, e1000534 (2009).
et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet.
89, 496–506 (2011).
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A.
Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science
324, 387–389 (2009).
et al. Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. PLoS Genet.
9, e1003487 (2013).