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Protective alleles and modifier variants in human health and disease

Key Points

  • Protective alleles confer protection against disease by disrupting protein function, typically via loss-of-function (LoF) effects.

  • Protective alleles have been identified for a range of complex disease phenotypes, such as Alzheimer disease and cardiometabolic disease, often within genes that contain known disease susceptibility variants.

  • Maintenance of health — and prevention of disease — are not attributable solely to individual protective alleles. Coding and non-coding regulatory regions of the genome (modifier variants) are likely to contribute to the overall genomic architecture of health, mimicking the situation with susceptibility to complex diseases.

  • Many protective alleles are low-frequency or rare alleles; studies that discovered these alleles have used large sample sizes across multi-ethnic cohorts, or specific founder populations in which individuals are more likely to harbour rare alleles and gene knockouts.

  • Discovery of LoF protective alleles has stimulated the development of drugs that mimic gene LoF or knockout effects for a range of phenotypes, with a successful example being the development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

  • The existence of protective LoF alleles and gene knockouts in otherwise healthy individuals suggests that drugs mimicking these LoF effects should demonstrate both efficacy and safety. However, evidence suggests that drug-induced gene knockout might not necessarily recapitulate the effects of LoF alleles.

Abstract

The combination of next-generation sequencing technologies and high-throughput genotyping platforms has revolutionized the pursuit of genetic variants that contribute towards disease. Furthermore, these technologies have provided invaluable insight into the genetic factors that prevent individuals from developing disease. Exploiting the evolutionary mechanisms that were designed by nature to help prevent disease is an attractive line of enquiry. Such efforts have the potential to generate a therapeutic target roadmap and rejuvenate the current drug-discovery pathway. By delineating the genomic factors that are protective against disease, there is potential to derive highly effective, genomically anchored medicines that assist in maintaining health.

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Figure 1: Population variation for common traits and how extreme phenotypes can provide unique insight into common disease biology.
Figure 2: Illustration of the close relationship between clinically relevant loss-of-function and gain-of-function alleles, using PCSK9 as an example.
Figure 3: Cis- and trans-acting modifier effects.

References

  1. Nadeau, J. H. & Topol, E. J. The genetics of health. Nat. Genet. 38, 1095–1098 (2006). Highlights the importance of protective alleles and modifier effects with respect to health.

    CAS  PubMed  Google Scholar 

  2. Mullard, A. New drugs cost US$2.6 billion to develop. Nat. Rev. Drug Discov. 13, 877 (2014).

    Google Scholar 

  3. Dubal, D. B. et al. Life extension factor klotho enhances cognition. Cell Rep. 7, 1065–1076 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kaiser, J. The hunt for missing genes. Science 344, 687–689 (2014).

    CAS  PubMed  Google Scholar 

  5. DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. The cost of drug development. N. Engl. J. Med. 372, 1972 (2015).

    PubMed  Google Scholar 

  6. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014).

    CAS  PubMed  Google Scholar 

  7. Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015). Provides empirical evidence supporting the role of human genetics in drug discovery.

    CAS  PubMed  Google Scholar 

  8. Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).

    CAS  PubMed  Google Scholar 

  9. Lobo, I. Same genetic mutation, different genetic disease phenotype. Nat. Educ. 1, 64 (2008).

    Google Scholar 

  10. Marmor, M., Hertzmark, K., Thomas, S. M., Halkitis, P. N. & Vogler, M. Resistance to HIV infection. J. Urban Health 83, 5–17 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    CAS  PubMed  Google Scholar 

  12. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

    CAS  PubMed  Google Scholar 

  13. Gulick, R. M. et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429–1441 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gu, W. G. Genome editing-based HIV therapies. Trends Biotechnol. 33, 172–179 (2015).

    CAS  PubMed  Google Scholar 

  16. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    CAS  PubMed  Google Scholar 

  17. Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005). One of the first papers highlighting the role of LoF mutations and protective traits.

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanna, S. et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet. 7, e1002198 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Navarese, E. P. et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann. Intern. Med. 163, 40–51 (2015).

    PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. Benn, M., Nordestgaard, B. G., Grande, P., Schnohr, P. & Tybjaerg-Hansen, A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J. Am. Coll. Cardiol. 55, 2833–2842 (2010).

    CAS  PubMed  Google Scholar 

  24. Hooper, A. J., Marais, A. D., Tanyanyiwa, D. M. & Burnett, J. R. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193, 445–448 (2007).

    CAS  PubMed  Google Scholar 

  25. Sabatine, M. S. et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).

    CAS  PubMed  Google Scholar 

  26. Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

    CAS  PubMed  Google Scholar 

  27. Institute for Clinical and Economic Review. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks: Draft Report CEPAC[online], (2015).

  28. Balemans, W. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543 (2001).

    CAS  PubMed  Google Scholar 

  29. Ominsky, M. S. et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 25, 948–959 (2010).

    CAS  PubMed  Google Scholar 

  30. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009).

    CAS  PubMed  Google Scholar 

  31. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014).

    CAS  PubMed  Google Scholar 

  32. Amgen. A Randomized Phase 3 Study to Evaluate 2 Different Formulations of Romosozumab in Postmenopausal Women With Osteoporosis (NCT02016716) ClinicalTrials.gov[online], (2015).

  33. Debette, S. et al. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nat. Genet. 47, 78–83 (2015).

    CAS  PubMed  Google Scholar 

  34. Fejerman, L. et al. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat. Commun. 5, 5260 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Dunstan, S. J. et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat. Genet. 46, 1333–1336 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Rautanen, A. et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir. Med. 3, 53–60 (2014).

    PubMed  Google Scholar 

  37. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Momozawa, Y. et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat. Genet. 43, 43–47 (2011).

    CAS  PubMed  Google Scholar 

  39. Rivas, M. A. et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Capon, F. et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum. Genet. 122, 201–206 (2007).

    CAS  PubMed  Google Scholar 

  41. Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

    PubMed  PubMed Central  Google Scholar 

  42. Rueda, B. et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 67, 1451–1454 (2008).

    CAS  PubMed  Google Scholar 

  43. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    CAS  PubMed  Google Scholar 

  44. Parkes, M., Cortes, A., van Heel, D. A. & Brown, M. A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661–673 (2013).

    CAS  PubMed  Google Scholar 

  45. Walsh, G. Biopharmaceutical benchmarks 2014. Nat. Biotechnol. 32, 992–1000 (2014).

    CAS  PubMed  Google Scholar 

  46. Thaci, D. et al. Secukinumab in psoriasis: randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE). Br. J. Dermatol. 173, 777–787 (2015).

    CAS  PubMed  Google Scholar 

  47. Griffiths, C. E. et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 386, 541–551 (2015).

    CAS  PubMed  Google Scholar 

  48. Carroll, J. Suicide stunner prompts Amgen to dump brodalumab, denting AstraZeneca's rep. FierceBiotech [online], (2015).

    Google Scholar 

  49. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    CAS  PubMed  Google Scholar 

  51. McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).

    CAS  PubMed  Google Scholar 

  55. Lim, E. T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. Benilova, I. et al. The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J. Biol. Chem. 289, 30977–30989 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Maloney, J. A. et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J. Biol. Chem. 289, 30990–31000 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kero, M. et al. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol. Aging 34, 1518.e1–1518.e3 (2013).

    CAS  Google Scholar 

  59. Wang, L. et al. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 72, 209–216 (2014).

    Google Scholar 

  60. Ting, S. K. et al. Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases. Neurobiol. Aging 34, 2441.e7–2441.e8 (2013).

    CAS  Google Scholar 

  61. Liu, Y. W. et al. Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol. Aging 35, 935.e11–935.e12 (2014).

    CAS  Google Scholar 

  62. Calcoen, D., Elias, L. & Yu, X. What does it take to produce a breakthrough drug? Nat. Rev. Drug Discov. 14, 161–162 (2015).

    PubMed  Google Scholar 

  63. Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res. Ther. 6, 89 (2014).

    PubMed  PubMed Central  Google Scholar 

  64. The Myocardial Infarction Genetics Consortium Investigators. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072–2082 (2014).

  65. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).

  66. Jorgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).

    PubMed  Google Scholar 

  67. Cannon, C. P. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. American Heart Association [online], (2014).

    Google Scholar 

  68. Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

    CAS  PubMed  Google Scholar 

  69. Ray, K. K. et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur. Heart J. 35, 960–968 (2014).

    PubMed  Google Scholar 

  70. Do, R. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Flannick, J. et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46, 357–363 (2014). Demonstrates the importance of human genetic studies across multiple ethnicities for the identification of protective mutations.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kirchhoff, K. et al. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51, 597–601 (2008).

    CAS  PubMed  Google Scholar 

  74. Dimas, A. S. et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes 63, 2158–2171 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Nicolson, T. J. et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58, 2070–2083 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tamaki, M. et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J. Clin. Invest. 123, 4513–4524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Peloso, G. M. et al. Phenotypic extremes in rare variant study designs. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2015.197 (2015).

  78. MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sidore, C. et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat. Genet. http://dx.doi.org/10.1038/ng.3368 (2015).

  80. Sulem, P. et al. Identification of a large set of rare complete human knockouts. Nat. Genet. 47, 448–452 (2015). Demonstrates the increased rate of LoF mutations within founder populations.

    CAS  PubMed  Google Scholar 

  81. Kirino, Y. et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Fejerman, L. et al. Genetic ancestry and risk of breast cancer among U.S. Latinas with breast cancer. Cancer Res. 68, 9723–9728 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Burchard, E. G. Medical research: missing patients. Nature 513, 301–302 (2014).

    CAS  PubMed  Google Scholar 

  84. Topol, E. J. Individualized medicine from prewomb to tomb. Cell 157, 241–253 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Becanovic, K. et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat. Neurosci. 18, 807–816 (2015).

    CAS  PubMed  Google Scholar 

  86. Moutsianas, L. et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat. Genet. 47, 1107–1113 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ariniello, L. et al. Frequency of “ACMG-56” variants in whole genomes of healthy elderly American Society for Human Genetics [online], abstr. (2014).

  88. Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Harrow, J. et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 22, 1760–1774 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Arking, D. E. et al. Association of human aging with a functional variant of klotho. Proc. Natl Acad. Sci. USA 99, 856–861 (2002).

    CAS  PubMed  Google Scholar 

  91. Campbell, I. M., Shaw, C. A., Stankiewicz, P. & Lupski, J. R. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. 31, 382–392 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Jones, M. J. & Jallepalli, P. V. Chromothripsis: chromosomes in crisis. Dev. Cell 23, 908–917 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. McDermott, D. H. et al. Chromothriptic cure of WHIM syndrome. Cell 160, 686–699 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Rossi, A. et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524, 230–233 (2015).

    CAS  PubMed  Google Scholar 

  95. Friend, S. H. & Schadt, E. E. Clues from the resilient. Science 344, 970–972 (2014).

    CAS  PubMed  Google Scholar 

  96. Kaiser, J. Google X sets out to define healthy human. Sciencemag.org[online], (2014).

  97. Cruchaga, C. et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505, 550–554 (2014).

    CAS  PubMed  Google Scholar 

  98. Chen, C. The secret to a healthy heart may lie in the genes of elite athletes. Bloomberg Business [online], (2015).

  99. Ye, Z. et al. Phenome-wide association studies (PheWASs) for functional variants. Eur. J. Hum. Genet. 23, 523–529 (2015).

    CAS  PubMed  Google Scholar 

  100. Topol, E. J. Cholesterol, racial variation and targeted medicines. Nat. Med. 11, 122–123 (2005).

    CAS  PubMed  Google Scholar 

  101. Cheung, V. G. & Spielman, R. S. Genetics of human gene expression: mapping DNA variants that influence gene expression. Nat. Rev. Genet. 10, 595–604 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. TV-45070 for the treatment of pain. XENON[online], (2015).

  103. Cox, J. J. et al. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. Hum. Mutat. 31, E1670–E1686 (2010).

    CAS  PubMed  Google Scholar 

  104. Yang, Y. et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Leipold, E. et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat. Genet. 45, 1399–1404 (2013).

    CAS  PubMed  Google Scholar 

  106. Woods, C. G., Babiker, M. O., Horrocks, I., Tolmie, J. & Kurth, I. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur. J. Hum. Genet. 23, 561–563 (2015).

    CAS  PubMed  Google Scholar 

  107. Recker, R. R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30, 216–224 (2015).

    CAS  PubMed  Google Scholar 

  108. Schuelke, M. et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350, 2682–2688 (2004).

    CAS  PubMed  Google Scholar 

  109. Pfizer initiates Phase 2 study of PF-06252616 in Duchenne muscular dystrophy. Pfizer [online], (2014).

  110. The COMPASS Study: a Study of Volanesorsen (Formally ISIS-APOCIIIRx) in Patients With Hypertriglyceridemia (NCT02300233) ClinicalTrials.gov[online], (2015).

  111. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    CAS  PubMed  Google Scholar 

  112. Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).

    CAS  PubMed  Google Scholar 

  113. Australo-Anglo-American Spondyloarthritis Consortium et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

  114. Goate, A. Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer's disease. J. Alzheimers Dis. 9, 341–347 (2006).

    CAS  PubMed  Google Scholar 

  115. Diogo, D. et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS ONE 10, e0122271 (2015).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Financial support was provided by the US National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Award UL1TR0001114. A.R.H. was supported through the UK National Institute for Health Research Academic Foundation Programme.

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Correspondence to Andrew R. Harper, Shalini Nayee or Eric J. Topol.

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Competing interests

E.J.T. consults for Illumina, Genapsys and Edico Genome and is a co-founder of Cypher Genomics. The other authors declare no competing interests.

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Glossary

Loss-of-function

(LoF). When an allele causes either partial or complete loss of gene expression. Complete loss of gene function is often termed a gene-knockout effect.

Next-generation sequencing

A high-throughput method of sequencing DNA, facilitating single-base-pair resolution across the entire genome.

Gain-of-function

(GoF). When an allele causes higher levels of gene expression than the 'normal' physiological level of gene expression.

Healthspan

The period of life during which an individual has optimal health, free from life-limiting disease.

Genome-editing techniques

Methods in which nucleases are used to induce specific variants within DNA, usually to bring about a phenotypic change (examples of techniques include CRISPR–Cas9 (clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9) and zinc-finger nucleases).

Monoclonal antibodies

Antibodies for a specific antigen made by identical immune cells cloned from a unique parent cell. Within pharmacology, monoclonal antibody-based drugs (denoted by the suffix -mab) are a form of biologic therapy that target specific antigen epitopes. These drugs were initially derived entirely from mouse antibodies, which resulted in high immunogenicity.

Humanized monoclonal antibody

A type of monoclonal antibody formed from mouse and human DNA sources. Humanized monoclonal antibody drugs consist primarily of human domains, with murine sequences being limited to the complementarity-determining region of the antibody, which results in lower immunogenicity than that associated with murine or chimeric monoclonal antibody drugs.

Variants with unknown significance

Variants for which there is insufficient information to determine whether the variant confers a benign or functional (pathogenic or protective) effect.

Allelic heterogeneity

The phenomenon in which multiple alleles within a locus confer the same phenotypic effect.

Founder populations

Populations that descend from a small number of 'founder' individuals, and therefore have reduced genetic diversity compared with outbred populations.

Haploinsufficiency

Where an individual has only one functional copy of a gene (rather than two functional copies), resulting in reduced levels of gene expression that alter the phenotype.

Transcription factor-binding site

A sequence of DNA that can be bound by transcription factors and thereby regulate transcription of coding regions of the genome.

Mosaicism

A term used to describe the occurrence of two or more cell populations that are derived from a single zygote but harbour different genotypes.

Morpholinos

Antisense oligonucleotides that are engineered to bind to specific mRNA sequences and inhibit protein synthesis, enabling researchers to determine the effects of reduced expression of the targeted gene.

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Harper, A., Nayee, S. & Topol, E. Protective alleles and modifier variants in human health and disease. Nat Rev Genet 16, 689–701 (2015). https://doi.org/10.1038/nrg4017

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