Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality

Annual Review of Genomics and Human Genetics

Volumn 16, Issue , 2015, Pages 327-350

  Evans, David M ^a,b   Davey Smith, George ^b  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b UNIVERSITY OF BRISTOL   (United Kingdom)

Author keywords

Causal analysis; Genetic epidemiology; Mining the phenome; Pharmacogenomics; Structural equation modeling

Indexed keywords

ARTICLE; BIDIRECTIONAL MENDELIAN RANDOMIZATION; DATA MINING; DRUG DEVELOPMENT; EFFECT SIZE; GENE EXPRESSION; GENE LINKAGE DISEQUILIBRIUM; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC EPIDEMIOLOGY; GENETIC RISK; GENETIC VARIABILITY; GENOTYPE; HUMAN; MENDELIAN RANDOMIZATION ANALYSIS; METABOLOMICS; NETWORK MENDELIAN RANDOMIZATION; PLEIOTROPY; QUANTITATIVE TRAIT LOCUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); SINGLE NUCLEOTIDE POLYMORPHISM; BLOOD PRESSURE; GENETIC VARIATION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; PHARMACOGENETICS; PROCEDURES; RANDOMIZATION;

CETP PROTEIN, HUMAN; CHOLESTEROL ESTER TRANSFER PROTEIN;

BLOOD PRESSURE; CHOLESTEROL ESTER TRANSFER PROTEINS; DRUG DISCOVERY; GENETIC VARIATION; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MENDELIAN RANDOMIZATION ANALYSIS; PHARMACOGENETICS; POLYMORPHISM, SINGLE NUCLEOTIDE; RANDOM ALLOCATION; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84940648792     PISSN: 15278204     EISSN: 1545293X     Source Type: Book Series    
DOI: 10.1146/annurev-genom-090314-050016     Document Type: Article

References (149)

1. ACCORD Study Group. 2010. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362:1563-74
2. Allin KH, Nordestgaard BG, Zacho J, Tybjaerg-Hansen A, Bojesen SE. 2010. C-reactive protein and the risk of cancer: a Mendelian randomization study. J. Natl. Cancer Inst. 102:202-6
3. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, et al. 2011. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 Nat. Genet. 43:246-52
4. Angrist J, Krueger A. 1992. Identification of causal effects using instrumental variables. J. Am. Stat. Assoc. 91:444-55
5. Angrist J, Pischke J. 2009. Mostly Harmless Econometrics: An Empiricist's Companion. Princeton,NJ: Princeton Univ. Press
6. Arrowsmith J, Miller P. 2013. Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov. 12:569
7. Ashburn TT, Thor KB. 2004. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3:673-83
8. Aten JE, Fuller TF, Lusis AJ, Horvath S. 2008. Using genetic markers to orient the edges in quantitative trait networks: the NEO software. BMC Syst. Biol. 2:34
9. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, et al. 2005. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267-78
10. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, et al. 2008. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40:955-62
11. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, et al. 2007. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357:2109-22
12. Beer NL, TribbleND, McCulloch LJ, Roos C, Johnson PR, et al. 2009. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18:4081-88
13. Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, et al. 2011. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 12:R10
14. Bernelot Moens SJ, van Capelleveen JC, Stroes ES. 2014. Inhibition of ApoCIII: the next PCSK9? Curr. Opin. Lipidol. 25:418-22
15. Bibikova M, Le J, Barnes B, Saedinia-Melnyk S, Zhou L, et al. 2009. Genome-wide DNA methylation profiling using Infinium R- assay. Epigenomics 1:177-200
16. Boraska V, Franklin CS, Floyd JA, Thornton LM, Huckins LM, et al. 2014. A genome-wide association study of anorexia nervosa. Mol. Psychiatry 19:1085-94
17. BrionMJ, Shakhbazov K, Visscher PM. 2013. Calculating statistical power in Mendelian randomization studies. Int. J. Epidemiol. 42:1497-501
18. Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, et al. 2015. An atlas of genetic correlations across human diseases and traits. BioRxiv. doi: 10.1101/014498
19. Burgess S, Butterworth A,Thompson SG. 2013. Mendelian randomization analysis withmultiple genetic variants using summarized data. Genet. Epidemiol. 37:658-65
20. Burgess S, Daniel RM, Butterworth AS, Thompson SG, EPIC-InterAct Consort. 2015. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int. J. Epidemiol. 44:484-95
21. Burgess S, Davies NM, Thompson SG (EPIC-InterAct Consort.). 2014. Instrumental variable analysis with a nonlinear exposure-outcome relationship. Epidemiology 25:877-85
22. Burgess S, Malarstig A. 2013. Using Mendelian randomization to assess and develop clinical interventions: limitations and benefits. J. Comp. Eff. Res. 2:209-12
23. Burgess S, Thompson SG. 2011. Bias in causal estimates from Mendelian randomization studies with weak instruments. Stat. Med. 30:1312-23
24. Burgess S, Thompson SG. 2013. Use of allele scores as instrumental variables for Mendelian randomization. Int. J. Epidemiol. 42:1134-44
25. C React. Protein Coron. Heart Dis. Genet. Collab. 2011. Association between C reactive protein and coronary heart disease: Mendelian randomisation analysis based on individual participant data. BMJ 342:d548
26. Cannon CP, Shah S,DanskyHM, Davidson M, Brinton EA, et al. 2010. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363:2406-15
27. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354:1264-72
28. Cohen JC, Stender S, Hobbs HH. 2014. APOC3, coronary disease, and complexities of Mendelian randomization. Cell Metab. 20:387-89
29. Colhoun HM, McKeigue PM, Davey Smith G. 2003. Problems of reporting genetic associations with complex outcomes. Lancet 361:865-72
30. Collins R. 2012. What makes UK Biobank special? Lancet 379:1173-74
31. Czeizel AE, Dudas I. 1992. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 327:1832-35
32. Davey Smith G. 2007. Capitalizing on Mendelian randomization to assess the effects of treatments. J. R. Soc. Med. 100:432-35
33. Davey Smith G. 2011. Random allocation in observational data: how small but robust effects could facilitate hypothesis-free causal inference. Epidemiology 22:460-63; discussion 467-68
34. Davey Smith G. 2011. Use of genetic markers and gene-diet interactions for interrogating populationlevel causal influences of diet on health. Genes Nutr. 6:27-43
35. Davey Smith G, Ebrahim S. 2003. "Mendelian randomization": Can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 32:1-22
36. Davey Smith G, Hemani G. 2014. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23:R89-98
37. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Day I, Ebrahim S. 2007. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLOS Med. 4:e352
38. Davies NM, von Hinke Kessler Scholder S, Farbmacher H, Burgess S,Windmeijer F, Davey Smith G. 2015. The many weak instruments problem and Mendelian randomization. Stat. Med. 34:454-68
39. Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, et al. 2011. Meta-analysis of genome-wide association studies in 80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123:731-38
40. Didelez V, Sheehan N. 2007. Mendelian randomization as an instrumental variable approach to causal inference. Stat. Methods Med. Res. 16:309-30
41. Efron B, Tibshirani RJ. 1993. An Introduction to the Bootstrap. New York: Chapman &Hall
42. EstradaK, StyrkarsdottirU,Evangelou E, Hsu YH, Duncan EL, et al. 2012. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 44:491-501
43. Evans DM, Brion MJ, Paternoster L, Kemp JP, McMahon G, et al. 2013. Mining the human phenome using allelic scores that index biological intermediates. PLOS Genet. 9:e1003919
44. Evans DM, Visscher PM, Wray NR. 2009. Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum. Mol. Genet. 18:3525-31
45. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, et al. 2010. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74:956-64
46. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, et al. 2012. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J. Am. Coll. Cardiol. 60:2631-39
47. Fernandez-Suarez XM, Rigden DJ, Galperin MY. 2014. The 2014 Nucleic Acids Research Database Issue and an updated NAR online Molecular Biology Database Collection. Nucleic Acids Res. 42:D1-6
48. Fieller EC. 1954. Some problems in interval estimation. J. R. Stat. Soc. B 16:175-85
49. Fisher RA. 1952. Statistical methods in genetics. Heredity 6:1-12 (Repr. 2010, Int. J. Epidemiol. 39:329-35
50. Fisk Green R, Byrne J, Crider KS, GallagherM, Koontz D, Berry RJ. 2013. Folate-related gene variants in Irish families affected by neural tube defects. Front. Genet. 4:223
51. Franke A, Balschun T, Sina C, Ellinghaus D, Hasler R, et al. 2010. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat. Genet. 42:292-94
52. Frost C, Thompson SG. 2002. Correcting for regression dilution bias: comparison of methods for a single predictor variable. J. R. Stat. Soc. A 163:173-89
53. Gage SH, Davey Smith G, Zammit S,HickmanM,MunafoMR. 2013. Using Mendelian randomisation to infer causality in depression and anxiety research. Depress. Anxiety 30:1185-93
54. Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, et al. 2008. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional diseasemodifying antirheumatic drug therapy study. Arthritis Rheum. 58:2968-80
55. Gibson WT. 2015. Beneficial metabolic phenotypes caused by loss-of-function APOC3 mutations. Clin. Genet. 87:31-32
56. Graham MJ, Lee RG, Bell TA III, Fu W, Mullick AE, et al. 2013. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112:1479-90
57. Hahn J, Hausman J, Kuersteiner G. 2004. Estimation with weak instruments: accuracy of higher-order bias and MSE approximations. Econ. J. 7:272-306
58. Heid IM, Jackson AU, Randall JC,Winkler TW, Qi L, et al. 2010. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 42:949-60
59. Hingorani A, Finan C, Sofat R, Overington JP, Casas JP. 2015. Mendelian randomization and genomics assisted drug development. In Mendelian Randomizing: How Genes Can Reveal the Biological and Environmental Causes of Disease, ed. G Davey Smith. Oxford, UK: Oxford Univ. Press. In press
60. Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, et al. 2014. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 349:g4164
61. Holmes MV, Lange LA, Palmer T, Lanktree MB, North KE, et al. 2014. Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis. Am. J. Hum. Genet. 94:198-208
62. HPS2-THRIVE Collab. Group. 2014. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371:203-12
63. Inoue A, Solon G. 2010. Two-sample instrumental variables estimators. Rev. Econ. Stat. 92:557-61
64. Interleukin-6 Recep.Mendel. Randomisation Anal. Consort. 2012. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet 379:1214-24
65. Jansen H, Samani NJ, Schunkert H. 2014. Mendelian randomization studies in coronary artery disease. Eur. Heart J. 35:1917-24
66. Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. 2014. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371:32-41
67. Katan MB. 1986. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 327:507-8 (Repr. 2004, Int. J. Epidemiol. 33:9
68. Katan MB. 2004. Commentary: Mendelian randomization, 18 years on. Int. J. Epidemiol. 33:10-11
69. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. 2005. Complement factor H polymorphism in age-related macular degeneration. Science 308:385-89
70. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, et al. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45:1452-58
71. Lango AllenH, Estrada K, LettreG, Berndt SI, Weedon MN, et al. 2010. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832-38
72. Li R, Tsaih SW, Shockley K, Stylianou IM,Wergedal J, et al. 2006. Structural model analysis ofmultiple quantitative traits. PLOS Genet. 2:e114
73. Lyngdoh T, Vuistiner P, Marques-Vidal P, Rousson V, Waeber G, et al. 2012. Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLOS ONE 7:e39321
74. Mailman MD, Feolo M, Jin Y, KimuraM, Tryka K, et al. 2007. TheNCBI dbGaP database of genotypes and phenotypes. Nat. Genet. 39:1181-86
75. Major Depress. Disord. Work. Group Psychiatr. GWAS Consort. 2013. A mega-analysis of genomewide association studies for major depressive disorder. Mol. Psychiatry 18:497-511
76. McGuinness B, O'Hare J, Craig D, Bullock R, Malouf R, Passmore P. 2010. Statins for the treatment of dementia. Cochrane Database Syst. Rev. 2010:CD007514
77. Millstein J, Zhang B, Zhu J, Schadt EE. 2009. Disentangling molecular relationships with a causal inference test. BMC Genet. 10:23
78. Minelli C, Thompson JR, Tobin MD, Abrams KR. 2004. An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization. Am. J. Epidemiol. 160:445-52
79. Morgan TH. 1919. Physical Basis of Heredity. Philadelphia: JB Lipincott
80. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, et al. 2012. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44:981-90
81. Munafo MR, Timofeeva MN,Morris RW, Prieto-Merino D, Sattar N, et al. 2012. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. J. Natl. Cancer Inst. 104:740-48
82. Myocard. Infarct. Genet. Consort. Investig. 2014. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371:2072-82
83. Nat. Genet. Eds. 2012. Asking for more. Nat. Genet. 44:733
84. Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, et al. 2015. Association ofCRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk. Int. J. Cancer 136:1181-92
85. Noveck R, Stroes ES, Flaim JD, Baker BF, Hughes S, et al. 2014. Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers. J. Am. Heart Assoc. 3:e001084
86. Omenn GS, Goodman GE, Thornquist MD, Balmes J, CullenMR, et al. 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334:1150-55
87. Osganian SK, StampferMJ, Rimm E, Spiegelman D, Hu FB, et al. 2003. Vitamin C and risk of coronary heart disease in women. J. Am. Coll. Cardiol. 42:246-52
88. Palmer TM, Lawlor DA, Harbord RM, Sheehan NA, Tobias JH, et al. 2012. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat. Methods Med. Res. 21:223-42
89. Palmer TM, Sterne JA, Harbord RM, Lawlor DA, Sheehan NA, et al. 2011. Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. Am. J. Epidemiol. 173:1392-403
90. Phillips AN, Davey SmithG. 1991. How independent are "independent" effects? Relative risk estimation when correlated exposures are measured imprecisely. J. Clin. Epidemiol. 44:1223-31
91. Pichler I, Del Greco MF, Gogele M, Lill CM, Bertram L, et al. 2013. Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study. PLOS Med. 10:e1001462
92. Pierce BL, Ahsan H, VanderweeleTJ. 2011. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int. J. Epidemiol. 40:740-52
93. Pierce BL, Burgess S. 2013. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol. 178:1177-84
94. Pierce BL, VanderWeele TJ. 2012. The effect of non-differential measurement error on bias, precision and power in Mendelian randomization studies. Int. J. Epidemiol. 41:1383-93
95. Plenge RM, Scolnick EM, Altshuler D. 2013. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12:581-94
96. Preiss D, Seshasai SR,Welsh P, Murphy SA,Ho JE, et al. 2011. Risk of incident diabetes with intensivedose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305:2556-64
97. Prizment AE, Folsom AR, Dreyfus J, Anderson KE, Visvanathan K, et al. 2013. Plasma C-reactive protein, genetic risk score, and risk of common cancers in the Atherosclerosis Risk in Communities study. Cancer Causes Control 24:2077-87
98. Proitsi P, Lupton MK, Velayudhan L, Newhouse S, Fogh I, et al. 2014. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. PLOS Med. 11:e1001713
99. Psychiatr. GWAS Consort. Bipolar Disord.Work. Group. 2011. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43:977-83
100. Relton CL, Davey Smith G. 2010. Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLOS Med. 7:e1000356
101. Relton CL, Davey Smith G. 2012. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int. J. Epidemiol. 41:161-76
102. Richmond RC, Davey Smith G, Ness AR, den Hoed M, McMahon G, Timpson NJ. 2014. Assessing causality in the association between child adiposity and physical activity levels: aMendelian randomization analysis. PLOS Med. 11:e1001618
103. Rietveld CA, Medland SE, Derringer J, Yang J, Esko T, et al. 2013. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science 340:1467-71
104. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. 1993. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328:1450-56
105. Rosa GJ, Valente BD, de los Campos G,WuXL,GianolaD, SilvaMA. 2011. Inferring causal phenotype networks using structural equation models. Genet. Sel. Evol. 43:6
106. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, et al. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-33
107. Sanseau P, Agarwal P, BarnesMR, Pastinen T, Richards JB, et al. 2012. Use of genome-wide association studies for drug repositioning. Nat. Biotechnol. 30:317-20
108. Sattar N, Preiss D,Murray HM, Welsh P, Buckley BM, et al. 2010. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375:735-42
109. Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, et al. 2005. An integrative genomics approach to infer causal associations between gene expression and disease. Nat. Genet. 37:710-17
110. Schizophr. Work. Group Psychiatr. Genomics Consort. 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421-27
111. Schunkert H, Konig IR, Kathiresan S, Reilly MP, Assimes TL, et al. 2011. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43:333-38
112. Schwartz GG, Olsson AG, AbtM, BallantyneCM, Barter PJ, et al. 2012. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367:2089-99
113. Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, et al. 2014. An atlas of genetic influences on human blood metabolites. Nat. Genet. 46:543-50
114. Shin SY, Petersen AK, Wahl S, Zhai G, Romisch-Margl W, et al. 2014. Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids. Genome Med. 6:25
115. Silverwood RJ, Holmes MV, Dale CE, Lawlor DA, Whittaker JC, et al. 2014. Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits. Int. J. Epidemiol. 43:1781-90
116. Smith JG, Luk K, Schulz CA, Engert JC, Do R, et al. 2014. Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA 312:1764-71
117. Sofat R, Hingorani AD, Smeeth L, Humphries SE, Talmud PJ, et al. 2010. Separating the mechanismbased and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation 121:52-62
118. Spearman C. 1904. The proof and measurement of association between two things. Am. J. Psychol. 15:72-101
119. Spearman C. 2010. The proof and measurement of association between two things. Int. J. Epidemiol. 39:1137-50 D
120. Stock J. 1997. Instrumental variables regression with weak instruments. Econometrica 65:557-86
121. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. 1993. Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 328:1444-49
122. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, et al. 2012. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366:1108-18
123. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, et al. 2015. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385:351-61
124. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, et al. 2010. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707-13
125. TG HDLWork. Group Exome Seq. Proj., Natl. Heart Lung Blood Inst. 2014. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371:22-31
126. Thakkinstian A, Chailurkit L, Warodomwichit D, RatanachaiwongW, Yamwong S, et al. 2014. Causal relationship between body mass index and fetuin-A level in the Asian population: a bidirectional Mendelian randomization study. Clin. Endocrinol. 81:197-203
127. Thomas DC, Lawlor DA, Thompson JR. 2007. Re: Estimation of bias in nongenetic observational studies using "Mendelian triangulation" by Bautista et al. Ann. Epidemiol. 17:511-13
128. Thrift AP, Shaheen NJ, GammonMD, Bernstein L, Reid BJ, et al. 2014. Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus: a Mendelian randomization study. J. Natl. Cancer Inst. 106:dju252
129. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, et al. 2005. C-reactive protein and its role in metabolic syndrome: Mendelian randomisation study. Lancet 366:1954-59
130. TimpsonNJ, Nordestgaard BG, Harbord RM, Zacho J, FraylingTM, et al. 2011. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int. J. Obes. 35:300-8
131. Tob. Genet. Consort. 2010. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42:441-47
132. Varbo A, Benn M, Davey SmithG,Timpson NJ, Tybjaerg-Hansen A, Nordestgaard BG. 2015. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ. Res. 116:665-73
133. Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, et al. 2013. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLOS Med. 10:e1001383
134. Visscher PM, Brown MA, McCarthy MI, Yang J. 2012. Five years of GWAS discovery. Am. J. Hum. Genet. 90:7-24
135. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, et al. 2012. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380:572-80
136. Waddington CH. 1942. The epigenotype. Endeavor 1:18-20 (Repr. 2012, Int. J. Epidemiol. 41:10-13
137. Wagner GP, Zhang J. 2011. The pleiotropic structure of the genotype-phenotype map: the evolvability of complex organisms. Nat. Rev. Genet. 12:204-13
138. Wald A. 1940. The fitting of straight lines if both variables are subject to error. Ann. Math. Stat. 11:284-300
139. Wang ZY,Zhang HY. 2013. Rational drug repositioning by medical genetics. Nat. Biotechnol. 31:1080-82
140. Wellcome Trust Case Control Consort. 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661-78
141. Welsh P, Polisecki E, RobertsonM, Jahn S, Buckley BM, et al. 2010. Unraveling the directional link between adiposity and inflammation: a bidirectionalMendelian randomization approach. J. Clin. Endocrinol. Metab. 95:93-99
142. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, et al. 2013. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45:1238-43
143. Wium-Andersen MK, Orsted DD, Nordestgaard BG. 2014. Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a Mendelian randomization study. Biol. Psychiatry 76:249-57
144. Wray NR, Yang J, Hayes BJ, Price AL, Goddard ME, Visscher PM. 2013. Pitfalls of predicting complex traits from SNPs. Nat. Rev. Genet. 14:507-15
145. Wurtz P, Kangas AJ, Soininen P, Lehtimaki T, Kahonen M, et al. 2013. Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a note on Mendelian randomization studies. J. Am. Coll. Cardiol. 62:1906-8
146. Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V. 2014. Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis. Metab. Brain Dis. 30:7-24
147. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, Gregori G, Penha FM, et al. 2014. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 121:693-701
148. Yin P, Voight BF. 2015. MeRP: a high-throughput pipeline for Mendelian randomization analysis. Bioinformatics 31:957-59
149. Zeilinger S, Kuhnel B, Klopp N, Baurecht H, Kleinschmidt A, et al. 2013. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLOS ONE 8:e63812