Two-step epigenetic mendelian randomization: A strategy for establishing the causal role of epigenetic processes in pathways to disease

International Journal of Epidemiology

Volumn 41, Issue 1, 2012, Pages 161-176

  Relton, Caroline L ^a   Davey Smith, George ^b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b UNIVERSITY OF BRISTOL   (United Kingdom)

Author keywords

Confounding; DNA methylation; Mediation; Mendelian randomization; Reverse causation

Indexed keywords

MESSENGER RNA; RIBOSOME RNA; TRANSFER RNA; UNTRANSLATED RNA;

BIOMARKER; DNA; METHYLATION; PRECIPITATION (CHEMISTRY); VULNERABILITY;

ARTICLE; CONFOUNDING VARIABLE; CONGENITAL HEART DISEASE; DNA METHYLATION; DNA MODIFICATION; ENVIRONMENTAL EXPOSURE; EPIGENETICS; GENETIC MARKER; GENETIC STABILITY; GENETIC VARIABILITY; GENOMICS; GENOTYPE; HUMAN; INHERITANCE; MEASUREMENT ERROR; MENDELIAN RANDOMIZATION ANALYSIS; METHODOLOGY; MITOSIS; OUTCOME ASSESSMENT; PHENOTYPE; POSTNATAL DEVELOPMENT; PRIORITY JOURNAL; RISK FACTOR;

DISEASE; DNA METHYLATION; ENVIRONMENTAL EXPOSURE; EPIDEMIOLOGIC RESEARCH DESIGN; EPIGENESIS, GENETIC; GENE-ENVIRONMENT INTERACTION; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MENDELIAN RANDOMIZATION ANALYSIS; RNA;

EID: 84858648623     PISSN: 03005771     EISSN: 14643685     Source Type: Journal    
DOI: 10.1093/ije/dyr233     Document Type: Article

References (139)

1. Hamm CA, Costa FF. The impact of epigenomics on future drug design and new therapies. Drug Discov Today 2011;16:626-35.
2. Feero WG, Guttmacher AE, Collins FS. Genomic medicine-an updated primer. N Engl J Med 2010;362: 2001-11.
3. Vineis P, Pearce NE. Genome-wide association studies may be misinterpreted: genes versus heritability. Carcinogenesis 2011;32:1295-98.
4. Le Fanu J. The disappointments of the double helix: a master theory. J R Soc Med 2010;103:43-45.
5. Ebrahim S, Davey Smith G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum Genet 2008;123:15-33.
6. Schadt EE. Molecular networks as sensors and drivers of common human diseases. Nature 2009;461:218-223.
7. Rockman MV. Reverse engineering the genotypephenotype map with natural genetic variation. Nature 2008;456:738-44.
8. Relton CL, Davey Smith G. Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med 2010;7:e1000356.
9. Lim DH, Maher ER. Genomic imprinting syndromes and cancer. Adv Genet 2010;70:145-75.
10. Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 2009;8:1056-72.
11. Kaminsky Z, Tochigi M, Jia P et al. A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry, 2011; doi:10.1038/mp.2011.64 [Epub].
12. Groom A, Potter C, Swan DC et al. Postnatal Growth and DNA Methylation Are Associated With Differential Gene Expression of the TACSTD2 Gene and Childhood Fat Mass. Diabetes 2012;61:391-400.
13. Godfrey KM, Sheppard A, Gluckman PD et al. Epigenetic gene promotermethylation at birth is associated with child's later adiposity. Diabetes 2011;60:1528-34.
14. Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA. Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genomics 2010;3:33.
15. Reynard LN, Bui C, Canty-Laird EG, Young DA, Loughlin J. Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Hum Mol Genet 2011;20:3450-60.
16. Hernandez DG, Nalls MA, Gibbs JR et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 2011;20: 1164-72.
17. Waddington CH. The epigenotype. Endeavour 1942;1: 18-20. Reprinted in Int J Epidemiol 2012;41:10-13.
18. Ho DH, Burggren WW. Epigenetics and transgenerational transfer: a physiological perspective. J Exp Biol 2010;213: 3-16.
19. Bird A. Perceptions of epigenetics. Nature 2007;447: 396-98.
20. Jablonka E, Raz G. Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. Q Rev Biol 2009;84: 131-76.
21. Jablonka E, Lamb MJ. Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life. Cambridge: MIT Press, 2005.
22. Ogbuanu IU, Zhang H, Karmaus W. Can we apply the Mendelian randomization methodology without considering epigenetic effects? Emerg Themes Epidemiol 2009;6:3.
23. Seong KH, Li D, Shimizu H, Nakamura R, Ishii S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 2011;145:1049-61.
24. Morgan DK, Whitelaw E. The case for transgenerational epigenetic inheritance in humans. Mamm Genome 2008; 19:394-97.
25. Rakyan VK, Chong S, Champ ME et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003;100:2538-43.
26. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010;467:963-66.
27. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 2009;27:351-57.
28. Skinner MK. Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics 2011;6:838-42.
29. Daxinger L, Whitelaw E. Transgenerational epigenetic inheritance: more questions than answers. Genome Res 2010; 20:1623-28.
30. Martin C, Zhang Y. Mechanisms of epigenetic inheritance. Curr Opin Cell Biol 2007;19:266-72.
31. Zaidi SK, Young DW, Montecino M et al. Bookmarking the genome: maintenance of epigenetic information. J Biol Chem 2011;286:18355-61.
32. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308:1466-69.
33. Matthews SG, Phillips DI. Transgenerational inheritance of stress pathology. Exp Neurol 2011; doi:10.1016/j.expneurol.2011.01.009 [Epub].
34. Sinclair KD, Karamitri A, Gardner DS. Dietary regulation of developmental programming in ruminants: epigenetic modifications in the germline. Soc Reprod Fertil Suppl 2010; 67:59-72.
35. Kappeler L, Meaney MJ. Epigenetics and parental effects. Bioessays 2010;32:818-27.
36. Crepin M, Dieu MC, Lejeune S et al. Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum Mutat 2011;33:180-188.
37. Vastenhouw NL, Brunschwig K, Okihara KL, Muller F, Tijsterman M, Plasterk RH. Gene expression: long-term gene silencing by RNAi. Nature 2006;442:882.
38. Carone BR, Fauquier L, Habib N et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010;143:1084-96.
39. Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 2008;32: 1373-79.
40. Li CC, Cropley JE, Cowley MJ, Preiss T, Martin DI, Suter CM. A sustained dietary change increases epigenetic variation in isogenic mice. PLoS Genet 2011;7:e1001380.
41. Day T, Bonduriansky R. A unified approach to the evolutionary consequences of genetic and nongenetic inheritance. Am Nat 2011;178:E18-36.
42. Davey Smith G. Epigenesis for Epidemiologists: does evodevo have implications for population health research and practice? Int J Epidemiol 2012;41:236-47.
43. Charlesworth D, Charlesworth B. Not quite a revolution. The Guardian Review, 3 September 2011, p. 15.
44. Haldane J. Some principles of causal analysis in genetics. Erkenntnis 1936;6:346-57.
45. Lynch M. The rate of polygenic mutation. Genet Res 1988; 51:137-48.
46. Francis R. Epigenetics: The Ultimate Mystery of Inheritance. New York: W.W. Norton & Company, Incorp, 2011.
47. Carey N. The Epigenetics Revolution: How Modern Biology is Rewriting Our Understanding of Genetics, Disease and Inheritance. London: Icon Books Ltd; 2011.
48. Bell JT, Pai AA, Pickrell JK et al. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 2011;12:R10.
49. Meaburn EL, Schalkwyk LC, Mill J. Allele-specific methylation in the human genome: implications for genetic studies of complex disease. Epigenetics 2010;5:578-82.
50. Rakyan VK, Down TA, Balding DJ, Beck S. Epigenomewide association studies for common human diseases. Nat Rev Genet 2011;12:529-41.
51. Laird PW. Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 2010;11:191-203.
52. Nelson HH, Marsit CJ, Kelsey KT. "Global methylation" in exposure biology and translational medical science. Environ Health Perspect 2011;119:1528-33.
53. Karimi M, Luttropp K, Ekstrom TJ. Global DNA methylation analysis using the luminometric methylation assay. Methods Mol Biol 2011;791:135-44.
54. Breitling LP, Yang R, Korn B, Burwinkel B, Brenner H. Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet 2011;88: 450-57.
55. Marsit CJ, Koestler DC, Christensen BC, Karagas MR, Houseman EA, Kelsey KT. DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol 2011;29:1133-39.
56. Teschendorff AE, Menon U, Gentry-Maharaj A et al. An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 2009;4:e8274.
57. Kneip C, Schmidt B, Seegebarth A et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol 2011; 6:1632-38.
58. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474: 609-15.
59. Davey Smith G. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings? Basic Clin Pharmacol Toxicol 2008;102: 245-56.
60. Davey Smith G, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22.
61. Li J, Burmeister M. Genetical genomics: combining genetics with gene expression analysis. Hum Mol Genet 2005;14(Spec No. 2):R163-69.
62. Schadt EE, Lamb J, Yang X et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 2005;37:710-17.
63. Greenland S. An introduction to instrumental variables for epidemiologists. Int J Epidemiol 2000;29:722-29.
64. Thomas DC, Conti DV. Commentary: the concept of 'Mendelian Randomization'. Int J Epidemiol 2004;33:21-25.
65. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133-63.
66. Davey Smith G, Harbord R, Ebrahim S. Fibrinogen, C-reactive protein and coronary heart disease: does Mendelian randomization suggest the associations are non-causal? QJM 2004;97:163-66.
67. Davey Smith G, Ebrahim S. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 2005;330:1076-79.
68. Sheehan NA, Didelez V, Burton PR, Tobin MD. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med 2008;5:e177.
69. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Day I, Ebrahim S. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLoS Med 2007;4:e352.
70. Palmer LJ, Cardon LR. Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet 2005;366:1223-34.
71. Ebrahim S, Lawlor DA, Shlomo YB et al. Alcohol dehydrogenase type 1C (ADH1C) variants, alcohol consumption traits, HDL-cholesterol and risk of coronary heart disease in women and men: British Women's Heart and Health Study and Caerphilly cohorts. Atherosclerosis 2008;196: 871-78.
72. Timpson NJ, Lawlor DA, Harbord RM et al. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 2005;366:1954-59.
73. Davey Smith G, Lawlor DA, Harbord R et al. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol 2005; 25:1051-56.
74. Casas JP, Shah T, Cooper J et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 2006;35:922-31.
75. Keavney B, Danesh J, Parish S et al. Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'. Int J Epidemiol 2006;35:935-43.
76. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301:2331-39.
77. Thanassoulis G, O'Donnell CJ. Mendelian randomization: nature's randomized trial in the post-genome era. JAMA 2009;301:2386-88.
78. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008;359:1897-908.
79. Timpson NJ, Wade KH, Davey Smith G. Mendelian Randomization: Application to Cardiovascular Disease. Current Hypertension Reports 2012;14:29-37.
80. Shah SH, de Lemos JA. Biomarkers and cardiovascular disease: determining causality and quantifying contribution to risk assessment. JAMA 2009;302:92-93.
81. Timpson NJ, Harbord R, Davey Smith G, Zacho J, Tybjaerg-Hansen A, Nordestgaard BG. Does greater adiposity increase blood pressure and hypertension risk?: Mendelian randomization using the FTO/MC4R genotype. Hypertension 2009;54:84-90.
82. Brennan P, McKay J, Moore L et al. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. Int J Epidemiol 2009;38:971-75.
83. Ding EL, Song Y, Manson JE et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009;361:1152-63.
84. Scott JA, Berkley JA, Mwangi I et al. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 2011;378:1316-23.
85. Jansen RC, Nap JP. Genetical genomics: the added value from segregation. Trends Genet 2001;17:388-91.
86. Moffatt MF, Kabesch M, Liang L et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:470-73.
87. Chen Y, Zhu J, Lum PY et al. Variations in DNA elucidate molecular networks that cause disease. Nature 2008; 52:429-35.
88. Emilsson V, Thorleifsson G, Zhang B et al. Genetics of gene expression and its effect on disease. Nature 2008; 452:423-28.
89. Drake TA, Schadt EE, Lusis AJ. Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice. Mamm Genome 2006;17: 466-79.
90. Davey Smith G. Random allocation in observational data: how small but robust effects could facilitate hypothesis-free causal inference. Epidemiology 2011;22: 460-63.
91. Wright MW, Bruford EA. Naming 'junk': human nonprotein coding RNA (ncRNA) gene nomenclature. Hum Genomics 2011;5:90-98.
92. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 2006; 441:469-74.
93. Orom UA, Shiekhattar R. Long non-coding RNAs and enhancers. Curr Opin Genet Dev 2011;21:194-98.
94. Feinberg AP, Irizarry RA, Fradin D et al. Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2010;2:49ra67.
95. Feinberg AP. Genome-scale approaches to the epigenetics of common human disease. Virchows Arch 2010; 456:13-21.
96. Feinberg AP, Irizarry RA. Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc Natl Acad Sci USA 2010;107 (Suppl. 1):1757-64.
97. Cloud J. Why your DNA isn't your destiny. Time Magazine, 6 January 2010.
98. Harrell E. The Human Epigenome. Time Magazine, 8 October 2009.
99. Haig D. Weismann Rules! OK? Epigenetics and the Lamarckian temptation. Biol Phil 2007;22:415-28.
100. Waterland RA, Travisano M, Tahiliani KG. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J 2007; 21:3380-85.
101. Jablonka E, Lamb MJ. The inheritance of acquired epigenetic variations. J Theor Biol 1989;139:69-83.
102. Waterland RA, Kellermayer R, Laritsky E et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet 2010;6: e1001252.
103. Kendrick SF, O'Boyle G, Mann J et al. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 2010;51:1988-97.
104. Hellman A, Chess A. Extensive sequence-influenced DNA methylation polymorphism in the human genome. Epigenetics Chromatin 2010;3:11.
105. Baccarelli A, Rienstra M, Benjamin EJ. Cardiovascular epigenetics: basic concepts and results from animal and human studies. Circ Cardiovasc Genet 2010;3: 567-73.
106. Gibbs JR, van der Brug MP, Hernandez DG et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 2010;6:e1000952.
107. Zhang D, Cheng L, Badner JA et al. Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet 2010;86:411-19.
108. Pai AA, Bell JT, Marioni JC, Pritchard JK, Gilad Y. A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genet 2011;7:e1001316.
109. Shoemaker R, Deng J, Wang W, Zhang K. Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res 2010;20:883-89.
110. Bell CG, Finer S, Lindgren CM et al. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 2010;5:e14040.
111. Robins JM, Greenland S. Identifiability and exchangeability for direct and indirect effects. Epidemiology 1992; 3:143-55.
112. Cole SR, Hernan MA. Fallibility in estimating direct effects. Int J Epidemiol 2002;31:163-65.
113. Blakely T. Commentary: estimating direct and indirect effects-fallible in theory, but in the real world? Int J Epidemiol 2002;31:166-67.
114. Hafeman DM. Confounding of indirect effects: a sensitivity analysis exploring the range of bias due to a cause common to both the mediator and the outcome. Am J Epidemiol 2011;174:710-17.
115. Cole SR. Illustrating bias due to conditioning on a collider. Int J Epidemiol 2010;39:417-20.
116. Timofeeva MN, McKay JD, Davey Smith G et al. Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC. Cancer Epidemiol Biomarkers Prev 2011;20:2250-61.
117. Zuccolo L, Fitz-Simon N, Gray R et al. A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women. Hum Mol Genet 2009;18:4457-66.
118. Chen L, Davey Smith G, Harbord RM, Lewis SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med 2008;5:e52.
119. Benn M, Tybjaerg-Hansen A, Stender S, Frikke-Schmidt R, Nordestgaard BG. Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study. J Natl Cancer Inst 2011;103:508-19.
120. Gerken T, Girard CA, Tung YC et al. The obesityassociated FTO gene encodes a 2-oxoglutaratedependent nucleic acid demethylase. Science 2007;318: 1469-72.
121. Brenet F, Moh M, Funk P et al. DNA methylation of the first exon is tightly linked to transcriptional silencing. PLoS One 2011;6:e14524.
122. Hansen KD, Timp W, Bravo HC et al. Increased methylation variation in epigenetic domains across cancer types. Nat Genet 2011;43:768-75.
123. Ji H, Ehrlich LI, Seita J et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 2010;467:338-42.
124. Irizarry RA, Ladd-Acosta C, Wen B et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009;41:178-86.
125. McGowan PO, Sasaki A, D'Alessio AC et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009;12: 342-48.
126. Cameron NM, Shahrokh D, Del Corpo A et al. Epigenetic programming of phenotypic variations in reproductive strategies in the rat through maternal care. J Neuroendocrinol 2008;20:795-801.
127. McGowan PO, Suderman M, Sasaki A et al. Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 2011;6:e14739.
128. Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003;361:865-72.
129. Sigurdsson MI, Smith AV, Bjornsson HT, Jonsson JJ. HapMap methylation-associated SNPs, markers of germline DNA methylation, positively correlate with regional levels of human meiotic recombination. Genome Res 2009; 19:581-89.
130. Tycko B. Allele-specific DNA methylation: beyond imprinting. Hum Mol Genet 2010;19:R210-20.
131. Bell CG. Integration of genomic and epigenomic DNA methylation data in common complex diseases by haplotype-specific methylation analysis. Personalized Medicine 2011;8:243-51.
132. Finer S, Holland ML, Nanty L, Rakyan VK. The hunt for the epiallele. Environ Mol Mutagen 2011;52:1-11.
133. Freathy RM, Kazeem GR, Morris RW et al. Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index. Int J Epidemiol 2011;40:1617-28.
134. Tobacco and Genetics Consortium. Genome-wide metaanalyses identify multiple loci associated with smoking behavior. Nat Genet 2010;42:441-47.
135. Terry MB, Delgado-Cruzata L, Vin-Raviv N, Wu HC, Santella RM. DNA methylation in white blood cells: association with risk factors in epidemiologic studies. Epigenetics 2011;6:828-37.
136. Sovio U, Mook-Kanamori DO, Warrington NM et al. Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development. PLoS Genet 2011;7: e1001307.
137. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665.
138. Timpson NJ, Sayers A, Davey-Smith G, Tobias JH. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J Bone Miner Res 2009;24:522-33.
139. Teslovich TM, Musunuru K, Smith AV et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-13.