Genetic Factors Are Not the Major Causes of Chronic Diseases

Stephen M Rappaport, Stephen M Rappaport

Abstract

The risk of acquiring a chronic disease is influenced by a person's genetics (G) and exposures received during life (the 'exposome', E) plus their interactions (G×E). Yet, investigators use genome-wide association studies (GWAS) to characterize G while relying on self-reported information to classify E. If E and G×E dominate disease risks, this imbalance obscures important causal factors. To estimate proportions of disease risk attributable to G (plus shared exposures), published data from Western European monozygotic (MZ) twins were used to estimate population attributable fractions (PAFs) for 28 chronic diseases. Genetic PAFs ranged from 3.4% for leukemia to 48.6% for asthma with a median value of 18.5%. Cancers had the lowest PAFs (median = 8.26%) while neurological (median = 26.1%) and lung (median = 33.6%) diseases had the highest PAFs. These PAFs were then linked with Western European mortality statistics to estimate deaths attributable to G for heart disease and nine cancer types. Of 1.53 million Western European deaths in 2000, 0.25 million (16.4%) could be attributed to genetics plus shared exposures. Given the modest influences of G-related factors on the risks of chronic diseases in MZ twins, the disparity in coverage of G and E in etiological research is problematic. To discover causes of disease, GWAS should be complemented with exposome-wide association studies (EWAS) that profile chemicals in biospecimens from incident disease cases and matched controls.

Conflict of interest statement

Competing Interests: The author has declared that no competing interests exist.

Figures

Fig 1. Population attributable fractions (PAFs) for…
Fig 1. Population attributable fractions (PAFs) for 28 disease phenotypes estimated from studies of monozygotic twins.
Sources of data and statistics are summarized in Table 2.
Fig 2. Numbers of Western-European deaths in…
Fig 2. Numbers of Western-European deaths in 2000 estimated for ischemic heart disease and nine cancer types (1.53 million total deaths from these causes).
The contributions attributed to genetics plus shared exposures are based on the population attributable fractions (PAFs) estimated from Western European monozygotic twins (Table 2).

References

    1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128. Epub 2012/12/19. doi: S0140-6736(12)61728-0 [pii] 10.1016/S0140-6736(12)61728-0 .
    1. Chakravarti A, Little P. Nature, nurture and human disease. Nature. 2003;421(6921):412–4. Epub 2003/01/24. 10.1038/nature01401 [pii]. .
    1. Hemminki K, Lorenzo Bermejo J, Forsti A. The balance between heritable and environmental aetiology of human disease. Nat Rev Genet. 2006;7(12):958–65. Epub 2006/12/02. doi: nrg2009 [pii] 10.1038/nrg2009 .
    1. Gannett L. What’s in a Cause?: The Pragmatic Dimensions of Genetic Explanations. Biology and Philosophy. 1999;14:349–74.
    1. Haga SB, Khoury MJ, Burke W. Genomic profiling to promote a healthy lifestyle: not ready for prime time. Nat Genet. 2003;34(4):347–50. 10.1038/ng0803-347 .
    1. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001–6. 10.1093/nar/gkt1229
    1. Chang CQ, Yesupriya A, Rowell JL, Pimentel CB, Clyne M, Gwinn M, et al. A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes. European journal of human genetics: EJHG. 2014;22(3):402–8. 10.1038/ejhg.2013.161
    1. Goldstein DB. Common genetic variation and human traits. N Engl J Med. 2009;360(17):1696–8. Epub 2009/04/17. doi: NEJMp0806284 [pii] 10.1056/NEJMp0806284 .
    1. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53. Epub 2009/10/09. doi: nature08494 [pii] 10.1038/nature08494
    1. Vineis P. Misuse of genetic data in environmental epidemiology. Ann N Y Acad Sci. 2006;1076:163–7. Epub 2006/11/23. doi: 1076/1/163 [pii] 10.1196/annals.1371.060 .
    1. Wild CP. Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1847–50. .
    1. Rappaport SM, Smith MT. Environment and disease risks. Science. 2010;330(6003):460–1. Epub 2010/10/23. doi: 330/6003/460 [pii] 10.1126/science.1192603 .
    1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224–60. Epub 2012/12/19. doi: S0140-6736(12)61766-8 [pii] 10.1016/S0140-6736(12)61766-8 .
    1. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66(6):1191–308. Epub 1981/06/01. .
    1. Wu S, Powers S, Zhu W, Hannun YA. Substantial contribution of extrinsic risk factors to cancer development. Nature. 2016;529(7584):43–7. 10.1038/nature16166 .
    1. Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A. The blood exposome and its role in discovering causes of disease. Environ Health Perspect. 2014;122(8):769–74. 10.1289/ehp.1308015 .
    1. Yang Q, Khoury MJ, Friedman J, Little J, Flanders WD. How many genes underlie the occurrence of common complex diseases in the population? Int J Epidemiol. 2005;34(5):1129–37. 10.1093/ije/dyi130 .
    1. Hemminki K, Czene K. Attributable risks of familial cancer from the Family-Cancer Database. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1638–44. Epub 2002/12/24. .
    1. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85. Epub 2000/07/13. .
    1. Hansen PS, Brix TH, Iachine I, Kyvik KO, Hegedus L. The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins. European journal of endocrinology / European Federation of Endocrine Societies. 2006;154(1):29–38. 10.1530/eje.1.02060 .
    1. Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. 1992;35(11):1060–7. .
    1. Katsika D, Grjibovski A, Einarsson C, Lammert F, Lichtenstein P, Marschall HU. Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs. Hepatology. 2005;41(5):1138–43. 10.1002/hep.20654 .
    1. Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA, et al. Heritability for Alzheimer's disease: the study of dementia in Swedish twins. The journals of gerontology Series A, Biological sciences and medical sciences. 1997;52(2):M117–25. .
    1. Sullivan PF, Evengard B, Jacks A, Pedersen NL. Twin analyses of chronic fatigue in a Swedish national sample. Psychological medicine. 2005;35(9):1327–36. 10.1017/S0033291705005222 .
    1. Cameron AJ, Lagergren J, Henriksson C, Nyren O, Locke GR 3rd, Pedersen NL. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology. 2002;122(1):55–9. .
    1. Bengtson MB, Ronning T, Vatn MH, Harris JR. Irritable bowel syndrome in twins: genes and environment. Gut. 2006;55(12):1754–9. 10.1136/gut.2006.097287
    1. Zdravkovic S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, De Faire U. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J Intern Med. 2002;252(3):247–54. .
    1. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke; a journal of cerebral circulation. 2002;33(3):769–74. .
    1. Algovik M, Nilsson E, Cnattingius S, Lichtenstein P, Nordenskjold A, Westgren M. Genetic influence on dystocia. Acta obstetricia et gynecologica Scandinavica. 2004;83(9):832–7. 10.1111/j.0001-6349.2004.00544.x .
    1. Altman D, Forsman M, Falconer C, Lichtenstein P. Genetic influence on stress urinary incontinence and pelvic organ prolapse. European urology. 2008;54(4):918–22. 10.1016/j.eururo.2007.12.004 .
    1. Mulder EJ, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin research: the official journal of the International Society for Twin Studies. 2003;6(5):422–31. 10.1375/136905203770326420 .
    1. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis and rheumatism. 2000;43(1):30–7. 10.1002/1529-0131(200001)43:1<30::AID-ANR5>;2-B .
    1. Thomsen SF, van der Sluis S, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. 2010;40(7):1054–61. 10.1111/j.1365-2222.2010.03525.x .
    1. Wirdefeldt K, Gatz M, Reynolds CA, Prescott CA, Pedersen NL. Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiology of aging. 2011;32(10):1923 e1-8. 10.1016/j.neurobiolaging.2011.02.017
    1. Ingebrigtsen T, Thomsen SF, Vestbo J, van der Sluis S, Kyvik KO, Silverman EK, et al. Genetic influences on Chronic Obstructive Pulmonary Disease—a twin study. Respiratory medicine. 2010;104(12):1890–5. 10.1016/j.rmed.2010.05.004 .
    1. Roberts NJ, Vogelstein JT, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE. The predictive capacity of personal genome sequencing. Sci Transl Med. 2012;4(133):133ra58 10.1126/scitranslmed.3003380
    1. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129(14):1483–92. 10.1161/CIRCULATIONAHA.113.004042
    1. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJ. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC cancer. 2002;2:37
    1. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2015;347(6217):78–81. 10.1126/science.1260825
    1. Rappaport SM. Biomarkers intersect with the exposome. Biomarkers. 2012;17(6):483–9. Epub 2012/06/08. 10.3109/1354750X.2012.691553 .
    1. Wild CP, Scalbert A, Herceg Z. Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Environmental and molecular mutagenesis. 2013;54(7):480–99. 10.1002/em.21777 .
    1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63. Epub 2011/04/09. doi: nature09922 [pii] 10.1038/nature09922
    1. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84. Epub 2013/04/26. 10.1056/NEJMoa1109400 .
    1. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85. Epub 2013/04/09. doi: nm.3145 [pii] 10.1038/nm.3145
    1. Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, et al. Plasma choline metabolites and colorectal cancer risk in the Women's Health Initiative Observational Study. Cancer research. 2014;74(24):7442–52. 10.1158/0008-5472.CAN-14-1835

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever