Nothing Special   »   [go: up one dir, main page]
Skip to main content

Advertisement

Springer Nature Link
Log in

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

  • Review
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of—that is randomized with respect to—the inheritance of other traits, according to Mendel’s law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers’ compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Al-Delaimy WK, Rexrode KM, Hu FB, Albert CM, Stampfer MJ, Willett WC, Manson JE (2004) Folate intake and risk of stroke among women. Stroke 35:1259–1263

    PubMed  CAS  Google Scholar 

  • Ames BN (1999) Cancer prevention and diet: help from single nucleotide polymorphisms. PNAS 96:12216–12218

    PubMed  CAS  Google Scholar 

  • Baird P (2000) Genetic technologies and achieving health for populations. Int J Health Serv 30:407–24

    PubMed  CAS  Google Scholar 

  • Baron DN, Dent CE, Harris H, Hart EW, Jepson JB (1956) Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features. Lancet 271:421–429

    PubMed  CAS  Google Scholar 

  • Baron JA, Cole BF, Sandler RS et al (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Eng J Med 348:891–899

    CAS  Google Scholar 

  • Bautista LE, Smeeth L, Hingorani AD, Casas JP (2006) Estimation of bias in nongenetic observational studies using “Mendelian Triangulation”. Ann Epidemiol 16:675–680

    PubMed  Google Scholar 

  • Bazzano LA, Reynolds K, Holder KN, He J (2006) Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 296:2720–2726

    PubMed  CAS  Google Scholar 

  • Berkowitz A (1999) Our genes, ourselves?. Bioscience 46:42–51

    Google Scholar 

  • Berkson J (1946) Limitations of the application of fourfold table analysis to hospital data. Biometrics Bull 2:47–53

    Google Scholar 

  • Bhatti P, Sigurdson AJ, Wang SS, Chen J, Rothman N, Hartge P, Bergen AW, Landi MT (2005) Genetic variation and willingness to participate in epidemiological research: data from three studies. Cancer Epidemiol Biomarkers Prev 14:2449–2453

    PubMed  Google Scholar 

  • Birge SJ, Keutmann HT, Cuatrecasas P, Whedon GD (1967) Osteoporosis, intestinal lactase deficiency and low dietary calcium intake. N Engl J Med 276:445–448

    Article  PubMed  CAS  Google Scholar 

  • Bochud M, Chiolero A, Elston RC, Paccaud F (2007) A cautionary note on the use of Mendelian randomization to infer causation in observational epidemiology. Int J Epidemiol. doi:10.1093/ije/dym186

    PubMed  Google Scholar 

  • Botto LD, Yang Q (2000) 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151:862–877

    PubMed  CAS  Google Scholar 

  • Brennan P (2002) Gene environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis 23(3):381–387

    PubMed  CAS  Google Scholar 

  • Brennan P (2004) Mendelian randomization and gene–environment interaction. Int J Epidemiol 33:17–21

    PubMed  Google Scholar 

  • Broer S, Cavanaugh JA, Rasko JEJ (2004) Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder. Transporters 33:233–236

    Google Scholar 

  • Brown MS, Goldstein JL (2006) Lowering LDL—not only how low, but how long? Science 311:1721–1723

    PubMed  CAS  Google Scholar 

  • Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, et al (2006) Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 35:922–931

    PubMed  Google Scholar 

  • Chao Y-C, Liou S-R, Chung Y-Y, Tang H-S, Hsu C-T, Li T-K, Yin S-J (1994) Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients. Hepatology 19:360–366

    PubMed  CAS  Google Scholar 

  • Cherry N, Mackness M, Durrington P et al (2002) Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip. Lancet 359:763–764

    PubMed  CAS  Google Scholar 

  • Cheverud JM (1988) A comparison of genetic and phenotypic correlations. Evolution 42:958–968

    Google Scholar 

  • Clayton D, McKeigue PM (2001) Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358:1356–1360

    PubMed  CAS  Google Scholar 

  • Cohen JC, Boerwinkle E, Mosely TH, Hobbs HH (2006) Sequence variations in PSCK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264–1272

    PubMed  CAS  Google Scholar 

  • Collins FS (1999) Medical and societal consequences of the Human Genome Project. N Engl J Med 341:28–37

    PubMed  CAS  Google Scholar 

  • Corazza GR, Benati G, Di Sario A et al (1995) Lactose intolerance and bone mass in postmenopausal Italian women. Br J Nutr 73:479–487

    PubMed  CAS  Google Scholar 

  • Correns CG (1900) Mendel’s Regel über das Verhalten der Nachkommenschaft der Bastarde. Berichte der Deutschen Botanischen Gesellschaft 8:158–68. English translation, G. Mendel’s law concerning the behavior of progeny of varietal hybrids. In: Stern and Sherwood, pp 119–32. WH Freeman and Co., San Francisco (1966)

  • Czeizel AE, Dudás I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832–1835

    Article  PubMed  CAS  Google Scholar 

  • Davey Smith G (2006) Cochrane lecture: randomised by (your) god: robust inference from an observational study design. J Epidemiol Community Health 60:382–388

    Google Scholar 

  • Davey Smith G (2007) Capitalising on Mendelian randomization to assess the effects of treatments. J R Soc Med 100:432–435

    PubMed  Google Scholar 

  • Davey Smith G, Ebrahim S (2002) Data dredging, bias, or confounding (editorial). BMJ 325:1437–1438

    Google Scholar 

  • Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32:1–22

    PubMed  Google Scholar 

  • Davey Smith G, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33:30–42

    Google Scholar 

  • Davey Smith G, Ebrahim S (2005a) What can Mendelian randomization tell us about modifiable behavioural and environmental exposures. BMJ 330:1076–1079

    PubMed  Google Scholar 

  • Davey Smith G, Ebrahim S (2005b) Folate supplementation and cardiovascular disease. Lancet 366:1679–1681

    PubMed  Google Scholar 

  • Davey Smith G, Ebrahim S (2007) Mendelian randomization: genetic variants as instruments for strengthening causal inference in observational studies. In: Vaupel JW, Weinstein M (eds) Bio-social surveys: current insight and future promise. The National Academies Press, National Research Council, Washington, DC

  • Davey Smith G, Phillips AN (1996) Inflation in epidemiology: ‘The proof and measurement of association between two things’ revisited. Br Med J 312:1659–1661

    Google Scholar 

  • Davey Smith G, Harbord R, Ebrahim S (2004) Fibrinogen, C-reactive protein and coronary heart disease: does Mendelian randomization suggest the associations are non-causal? Q J Med 97:163–166

    CAS  Google Scholar 

  • Davey Smith G, Ebrahim S, Lewis S, Hansell A, Palmer LJ, Burton P (2005a) Genetic epidemiology and public health: hope, hype, and future prospects. Lancet 366:1484–1498

    PubMed  Google Scholar 

  • Davey Smith G, Lawlor D, Harbord R, Timpson N, Rumley A, Lowe G, Day I, Ebrahim S (2005b) Association of C-reactive protein with blood pressure and hypertension: lifecourse confounding and Mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol 25:1051–1056

    PubMed  Google Scholar 

  • Davey Smith G, Harbord R, Milton J, Ebrahim S, Sterne JAC (2005c) Does elevated plasma fibrinogen increase the risk of coronary heart disease?: evidence from a meta-analysis of Genetic Association Studies. Arterioscler Thromb Vasc Biol 25:2228–2233

    Google Scholar 

  • Davey Smith G, Lawlor D, Harbord R, Timpson N, Day I, Ebrahim S (2007) Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLoS Medicine (in press)

  • Elwood PC, Yarnell JWG, Burr ML et al (1991) Epidemiological studies of cardiovascular disease: progress report VII. MRC Epidemiology Unit, Cardiff

  • Enomoto N, Takase S, Yasuhara M, Takada A (1991) Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res 15:141–144

    PubMed  CAS  Google Scholar 

  • Færgeman O (2003) Coronary artery disease: genes drugs and the agricultural connection. Elseveir, Netherlands

    Google Scholar 

  • Fallon UB, Ben-Shlomo Y, Davey Smith G (2001) Homocysteine and coronary heart disease. Heart Online, March 14th. http://heart.bmjjournals.com/cgi/eletters/85/2/153

  • Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894

    PubMed  CAS  Google Scholar 

  • Gause GF (1942) The relation of adaptability to adaption. Q Rev Biol 17:99–114

    Google Scholar 

  • Goldschmidt RB (1938) Physiological genetics. McGraw-Hill, New York

    Google Scholar 

  • Gray R, Wheatley K (1991) How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 7(suppl 3):9–12

    PubMed  Google Scholar 

  • Gutjahr E, Gmel G, Rehm J (2001) Relation between average alcohol consumption and disease: an overview. Eur Addict Res 7:117–27

    PubMed  CAS  Google Scholar 

  • Guy JT (1993) Oral manifestations of systematic disease. In: Cummings CW et al (eds) Otolaryngology—head and neck surgery, vol 2. Mosby, St Louis

  • Hart C, Davey Smith G, Hole D, Hawthorne V (1999) Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of Scottish men with 21 years of follow up. Br Med J 318:1725–1729

    CAS  Google Scholar 

  • Hasin D, Aharonovich E, Liu X, Mamman Z, Matseoane K, Carr L, Li TK (2002) Alcohol and ADH2 in Israel: Ashkenazis, Sephardics, and recent Russian immigrants. Am J Psychiatry 159:1432–1434

    PubMed  Google Scholar 

  • He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, Ascherio A (2004) Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 35:169–174

    PubMed  CAS  Google Scholar 

  • Heart Protection Study Collaborative Group (writing committee: Collins R, Armitage J, Parish S, Sleight, Peto R) (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22

    Google Scholar 

  • Higuchi S, Matsuushita S, Imazeki H, Kinoshita T, Takagi S, Kono H (1994) Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet 343:741–742

    PubMed  CAS  Google Scholar 

  • Hingorani A, Humphries S (2005) Nature’s randomised trials. Lancet 366:1906–1908

    PubMed  Google Scholar 

  • Holtzman NA (2001) Putting the search for genes in perspective. Int J Health Serv 31:445

    PubMed  CAS  Google Scholar 

  • Honkanen R, Pulkkinen P, Järvinen R, Kröger H, Lindstedt K, Tuppurainen M, Uusitupa M (1996) Does lactose intolerance predispose to low bone density? A population-based study of perimenopausal Finnish women. Bone 19:23–28

    PubMed  CAS  Google Scholar 

  • Honkanen R, Kröger H, Alhava E, Turpeinen P, Tuppurainen M, Saarikoski S (1997) Lactose intolerance associated with fractures of weight-bearing bones in Finnish Women aged 38–57 years. Bone 21:473–477

    PubMed  CAS  Google Scholar 

  • Hyppönen E, Davey Smith G, Power C (2007) Vitamin D status and self-perceived health: conventional and Mendelian randomisation approaches. J Epidemiol Community Health 61(suppl1):A14

    Google Scholar 

  • Jablonka-Tavory E (1982) Genocopies and the evolution of interdependence. Evol Theory 6:167–170

    Google Scholar 

  • Jousilahti P, Salomaa V (2004) Fibrinogen, social position, and Mendelian randomisation. J Epidemiol Community Health 58:883

    PubMed  Google Scholar 

  • Juul K, Tybjaerg-Hansen A, Marklund S, Heegaard NHH, Steffensen R, Sillesen H, Jensen G, Nordestgaard BG (2004) Genetically reduced antioxidative protection and increased ischaemic heart disease risk: the Copenhagen city heart study. Circulation 109:59–65

    PubMed  CAS  Google Scholar 

  • Katan MB (1986) Apoliopoprotein E isoforms, serum cholesterol, and cancer. Lancet I:507–508 (reprinted IJE 2004;34:9)

    Google Scholar 

  • Keavney B (2002) Genetic epidemiological studies of coronary heart disease. Int J Epidemiol 31:730–736

    PubMed  Google Scholar 

  • Kelada SN, Eaton DL, Wang SS, Rothman NR, Khoury MJ (2003) The role of genetic polymorphisms in environmental health. Environ Health Perspect 111:1055–1064

    PubMed  CAS  Google Scholar 

  • Khoury M, Beaty TH, Cohen BH (1993) Fundamentals of genetic epidemiology. Oxford University Press, Oxford, p 13, 126

  • Khoury M, Little J, Burke W (2004) Human genome epidemiology. Oxford University Press, Oxford

    Google Scholar 

  • Khoury M, Davis R, Gwinn M, Lindegren ML, Yoon P (2005) Do we need genomic research for the prevention of common diseases with environmental causes? Am J Epidemiol 161:799–805

    PubMed  Google Scholar 

  • Khoury MJ, Little J, Gwinn M, Ioannidis JPA (2007) On the synthesis and interpretation of consistent but weak gene–disease association studies in the era of genome-wide association studies. Int J Epidemiol 36:439–445

    PubMed  Google Scholar 

  • Kivimäki M, Lawlor DA, Davey Smith G, Eklund C, Murme M, Lehtimäki T, Viikari JS, Raitakari OT (2007) Variants in the CRP Gene as a measure of lifelong differences in average C-reactive protein levels. The cardiovascular risk in young Finns study, 1980–2001. Am J Epidemiol 166:760–764

    PubMed  Google Scholar 

  • Kraut JA, Sachs G (2005) Hartnup disorder: unravelling the mystery. Trends Pharmacol Sci 26:53–55

    PubMed  CAS  Google Scholar 

  • Kune GA, Kune S, Watson LF (1988) Colorectal cancer risk, chronic illnesses, operations and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 48:4399–4404

    PubMed  CAS  Google Scholar 

  • Lawlor DA, Harbord R, Sterne JAC, Timpson N, Davey Smith G (2007) Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stats Med. doi: 10.1002/sim.3034

    Google Scholar 

  • Lawlor DA, Davey Smith G, Bruckdorfer KR et al (2004) Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 363:1724–1727

    PubMed  Google Scholar 

  • LDL receptor mutation catalogue. http://www.ucl.ac.uk/fh. Accessed 16 Dec 2003

  • Leimar O, Hammerstein P, Van Dooren TJM (2006) A new perspective on developmental plasticity and the principles of adaptive morph determination. Am Nat 167:367–376

    PubMed  Google Scholar 

  • Lenz W (1973) Phenocopies. J Med Genet 10:34–48

    PubMed  CAS  Google Scholar 

  • Lewis S, Davey Smith G (2005) Alcohol, ALDH2 and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev 14:1967–1971

    PubMed  CAS  Google Scholar 

  • Lewis SJ, Ebrahim S, Davey Smith G (2005) Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 331:1053

    PubMed  CAS  Google Scholar 

  • Li R, Tsaih SW, Shockley K, Stylianou IM, Wergedal J,Paigen B, Churchill GA (2006) Structural model analysis of multiple quantative traits. PLoS Genet 2:1046–1057

    CAS  Google Scholar 

  • Lin HJ, Lakkides KM, Keku TO, Reddy ST, Louie AD et al (2002) Prostaglandin H Synthase 2 variant (Val511Ala) in African Americans may reduce the risk for colorectal neoplasia. Cancer Epidemiol Biomarkers Prev 11:1305–1315

    PubMed  CAS  Google Scholar 

  • Lipp HP, Schwegler H, Crusio WE, Wolfer DP, Leisinger-Trigona MC, Heimrich B, Driscoll P (1989) Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behaviour: a non-invasive approach. Experientia 45:845–859

    PubMed  CAS  Google Scholar 

  • Lower GM, Nilsson T, Nelson CE et al (1979) N-acetylransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Environ Health Perspect 29:71–79

    PubMed  CAS  Google Scholar 

  • Marks D, Thorogood M, Neil HAW, Humphries SE (2003) A review on diagnosis, natural history and treatment of familial hypercholesterolaemia. Atherosclerosis 168:1–14

    PubMed  CAS  Google Scholar 

  • McGrath J (1999) Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 40:173–177

    PubMed  CAS  Google Scholar 

  • McNamara JJ, Molot MA, Stremple JF, Cutting RT (1971) Coronary artery disease in combat casualties in Vietnam. JAMA 216:1185–1187

    PubMed  CAS  Google Scholar 

  • Meade TW, Humpries SE, De Stavola BL (2006) Commentary: fibrinogen and coronary heart disease—test of causality by “Mendelian” randomization by Keavney et al. Int J Epidemiol 35:944–947

    PubMed  Google Scholar 

  • Memik F (2003) Alcohol and esophageal cancer, is there an exaggerated accusation? Hepatogastroenterology 54:1953–1955

    Google Scholar 

  • Mendel G (1866) Experiments in plant hybridization. http://www.mendelweb.org/archive/Mendel.Experiments.txt

  • 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 160:445–452

    PubMed  Google Scholar 

  • Morgan TH (1913) Heredity and sex. Columbia University Press, New York

    Google Scholar 

  • Morgan TH (1918) Physical basis of heredity

  • MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 338:131–137

    Google Scholar 

  • Myant NB (1993) Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 104:1–18

    PubMed  CAS  Google Scholar 

  • Ness AR, Davey Smith G, Hart C (2001) Milk, coronary heart disease and mortality. J Epidemiol Community Health 55:379–382

    PubMed  CAS  Google Scholar 

  • Newcomer AD, Hodgson SF, Douglas MD, Thomas PJ (1978) Lactase deficiency: prevalence in osteoporosis. Ann Intern Med 89:218–220

    PubMed  CAS  Google Scholar 

  • Nitsch D, Molokhia M, Smeeth L, De Stavola B, Whittaker JC, Leon DA (2006) Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 163:397–403

    PubMed  Google Scholar 

  • Obermayer-Pietsch BM, Bonelli CM, Walter DE, Kuhn RJ, Fahrleitner-Pammer A, Berghold A, Goessler W, Stepan V, Dobnig H, Leb G, Renner W (2004) Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res 19:42–47

    PubMed  Google Scholar 

  • Olby RC (1966) Origins of Mendelism. Constable London

  • Palmer L, Cardon L (2005) Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet 366:1223–1234

    PubMed  CAS  Google Scholar 

  • Peto R (1976) Two properties of multiple regression analysis and regression to the mean (and regression from the mean). In: Fletcher CM, Peto R, Tinker CM, Speizer FE (eds) The natural history of chronic bronchitis and emphysema: an eight year study of early chronic obstructive lung disease in working men in London. Oxford University Press, Oxford, pp 218–223

    Google Scholar 

  • Reynolds K, Lewis LB, Nolen JDL, Kinney GL, Sathya B, He J (2003) Alcohol consumption and risk of stroke: a meta-analysis. JAMA 289:579–588

    PubMed  Google Scholar 

  • Roderic TH, Wimer RE, Wimer CC (1976) Genetic manipulation of neuroanatomical traits. In: Petrinovich L, McGaugh JL (eds) Knowing thinking and believing. Plenum, New York

    Google Scholar 

  • Rose G (1982) Incubation period of coronary heart disease. BMJ 284:1600–1601

    PubMed  CAS  Google Scholar 

  • Rose S (1995) The rise of neurogenetic determinism. Nature 373:380–382

    PubMed  CAS  Google Scholar 

  • Rothman N, Wacholder S, Caporaso NE, Garcia-Closas M, Buetow K, Fraumeni JF (2001) The use of common genetic polymorphisms to enhance the epidemiologic study of environmental carcinogens. Biochim Biophys Acta 1471:C1–C10

    PubMed  CAS  Google Scholar 

  • Sandler RS, Galanko JC, Murray SC, Helm JF, Woosley JT (1998) Aspirin and nonsteroidal anti-inflammatory gents and risk for colorectal adenomas. Gastroenterology 114:441–447

    PubMed  CAS  Google Scholar 

  • Sandler RS, Halabi S, Baron JA et al (2003) A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348:883–890

    PubMed  CAS  Google Scholar 

  • Scientific Steering Committee on behalf of the Simon Broome Register Group (1991) Risk of fatal coronary heart disease in familial hyper-cholesterolaemia. BMJ 303:893–896

    Google Scholar 

  • Scriver CR (1988) Nutrient–gene interactions: the gene is not the disease and vice versa. Am J Clin Nutr 48:1505–1509

    PubMed  CAS  Google Scholar 

  • Scriver CR, Mahon B, Levy HL (1987) The Hartnup phenotypeL Mendelain transport disorder, multifactorial disease. Am J Hum Genet 40:401–412

    PubMed  CAS  Google Scholar 

  • Shaper AG, Wannamethee G, Walker M (1991) Milk, butter and heart disease. BMJ 302:785–786

    Article  PubMed  CAS  Google Scholar 

  • Shepherd J, Cobbe SM, Ford I et al for the West of Scotland Coronary Prevention Study Group (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301–1307

    PubMed  CAS  Google Scholar 

  • Slack J (1969) Risks of ischaemic heart disease in familial hyperlipoproteinaemic states. Lancet 2:1380–1382

    PubMed  CAS  Google Scholar 

  • Snyder LH (1959) Fifty years of medical genetics. Science 129:7–13

    PubMed  CAS  Google Scholar 

  • Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJ (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591

    PubMed  CAS  Google Scholar 

  • Spearman C (1904) The proof and measurement of association between two things. Am J Psychol 15:72–101

    Google Scholar 

  • Steinberg D (2004) Thematic review series: the pathogensis of athersclerosis. An interpretive history of the cholesterol controversy: part 1. J Lipid Res 45:1583–1593

    PubMed  CAS  Google Scholar 

  • Steinberg D (2005) Thematic review series: the pathogensis of athersclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholestrolemia to cornary disease in humans. J Lipid Res 46:179–190

    PubMed  CAS  Google Scholar 

  • Strohman RC (1993) Ancient genomes, wise bodies, unhealthy people: the limits of a genetic paradigm in biology and medicine. Perspect Biol Med 37:112–145

    PubMed  CAS  Google Scholar 

  • Takagi S, Iwai N, Yamauchi R, Kojima S, Yasuno S, Baba T, Terashima M, Tsutsumi Y, Suzuki S, Morii I, Hanai S, Ono K, Baba S, Tomoike H, Kawamura A, Miyazaki S (2002) Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese Mmen. Hypertens Res 25:677–681

    PubMed  CAS  Google Scholar 

  • Keavney B, Danesh J, Parish S, Palmer A, Clark S, Youngman L, Delépine M, Lathrop M, Peto R, Collins R The International Studies of Infarct Survival (ISIS) Collaborators (2006) Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’. Int J Epidemiol 35:935–943

    PubMed  Google Scholar 

  • Thomas DC, Lawlor DA, Thompson JR (2007) Re: Estimation of bias in nongenetic observational studies using “Mendelian Triangulation”. Ann Epidemiol 17:511–513

    PubMed  Google Scholar 

  • Thun MJ, Peto R, Lopez AD (1997) Alcohol consumption and mortality among middle-aged and elderly US adults. New Engl J Med 337:1705–1714

    PubMed  CAS  Google Scholar 

  • Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day INM, Palmer LJ, Hattersley AT, Ebrahim S, Lowe GDO, Rumley A, Davey Smith G (2005) C-reactive protein and its role in metabolic syndrome: mendelian randomization study. Lancet 366:1954–1959

    PubMed  CAS  Google Scholar 

  • Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 294:565–575

    Google Scholar 

  • Tybjaerg-Hansen A, Humphries SE (1992) Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 96:91–107

    PubMed  CAS  Google Scholar 

  • Tybjærg-Hansen A, Steffenson R, Meinertz H, Schnohr P, Nordestgaard BG (1998) Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. New Engl J Med 338:1577–1584

    PubMed  Google Scholar 

  • Van der Bom JG, De Maat MPM, Bots ML, Haverkate F, De Jong PTVM, Hofman A, Kluft C, Grobbee DE (1998) Elevated plasma fibrinogen. Cause or consequence of cardiovascular disease? Arterioscler Thromb Vasc Biol 18:621–625

    PubMed  Google Scholar 

  • Wald DS, Law M, Morris JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325:1202–1206

    PubMed  Google Scholar 

  • Weimer RE (1973) Dissociation of phenotypic correlation: response to posttrial etherization and to temporal distribution of practice trials. Behav Genet 3:379–386

    Google Scholar 

  • Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Google Scholar 

  • West-Eberhard MJ (2003) Developmental plasticity and evolution. Oxford University Press, Oxford

    Google Scholar 

  • Wheatley K, Gray R (2004) Commentary: Mendelian randomization—an update on its use to evaluate allogeneic stem cell transplantation in leukaemia. Int J Epidemiol 33:15–17

    PubMed  Google Scholar 

  • Williams RS, Wagner PD (2000) Transgenic animals in integrative biology: approaches and interpretations of outcome. J Appl Physiol 88:1119–1126

    PubMed  CAS  Google Scholar 

  • Wolf U (1995) The genetic contribution to the phenotype. Hum Genet 95:127–148

    PubMed  CAS  Google Scholar 

  • Youngman LD, Keavney BD, Palmer A et al (2000) Plasma fibrinogen and fibrinogen genotypes in 4685 cases of myocardial infarction and in 6002 controls: test of causality by “Mendelian randomization”. Circulation 102(suppl II):31–32

    Google Scholar 

  • Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341

    PubMed  CAS  Google Scholar 

  • Zoccali C, Testa A, Spoto B, Tripepi G, Mallamaci F (2006) Mendelian randomization: a new approach to studying epidemiology in ESRD. Am J Kidney Dis 47:332–341

    PubMed  Google Scholar 

  • Zuckerkandl E, Villet R (1988) Concentration—affinity equlivalence in gene regulation: convergence and environmental effects. Proc Natl Acad Sci USA 85:4784–4788

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Noncommunicable Diseases Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT, London, UK

    Shah Ebrahim

  2. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, BS8 2PR, Bristol, UK

    George Davey Smith

Authors
  1. Shah Ebrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Davey Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shah Ebrahim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ebrahim, S., Davey Smith, G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?. Hum Genet 123, 15–33 (2008). https://doi.org/10.1007/s00439-007-0448-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0448-6

Keywords

Search

Navigation