IJE Advance Access published online on July 25, 2005
International Journal of Epidemiology, doi:10.1093/ije/dyi130
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA
* To whom correspondence should be addressed. Background Most common human diseases are due to complex interactions among multiple genetic variants and environmental risk factors. There is debate over whether variants of a relatively small number of genes, each with weak or modest individual effects, account for a large proportion of common diseases in the population, or whether a large number of rare variants with large effects underlie genetic susceptibility to these diseases. It is not clear how many genes are necessary to account for an appreciable population-attributable fraction of these diseases. Methods In this analysis, we estimated the number of disease susceptibility genes needed to account for varying population attributable fractions of a common complex disease, taking into account the genotype prevalence, risk ratios for individual genes, and the model of gene-gene interactions (additive or multiplicative). Results Very large numbers of rare genotypes (e.g. those with frequencies of 1 per 5000 or less) are needed to explain 50% of a common disease in the population, even if the individual risk ratios are large (RR = 10-20). On the other hand, only Conclusions Our results suggest that a limited number of disease susceptibility genes with common variants can explain a major proportion of common complex diseases in the population. Our findings should help focus the search for common genetic variants that provide the most important predispositions to complex human diseases.
Accepted May 31, 2005
Original paper
How many genes underlie the occurrence of common complex diseases in the population?
2 Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA
3 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
4 Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada
5 Department of Epidemiology, School of Public Health, Emory University, Atlanta, GA, USA
Quanhe Yang, E-mail: qay0{at}cdc.gov
Abstract 
20 genes are usually needed to explain 50% of the burden of a disease in the population if the predisposing genotypes are common (
25%), even if the individual risk ratios are relatively small (RR = 1.2-1.5).
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M Mamtani, B Rovin, R Brey, J F Camargo, H Kulkarni, M Herrera, P Correa, S Holliday, J-M Anaya, and S K Ahuja CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus Ann Rheum Dis, August 1, 2008; 67(8): 1076 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-H. Yang, L. D Botto, M. Gallagher, J. Friedman, C. L Sanders, D. Koontz, S. Nikolova, J D. Erickson, and K. Steinberg Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank Am. J. Clinical Nutrition, July 1, 2008; 88(1): 232 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. V. Nguyen Genetics of Osteoporosis: From Population Association to Individualized Prognosis of Fracture IBMS BoneKEy, June 1, 2008; 5(6): 212 - 221. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sawcer The complex genetics of multiple sclerosis: pitfalls and prospects Brain, May 18, 2008; (2008) awn081v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Sanderson, S. E. Humphries, C. Hubbart, E. Hughes, M. J. Jarvis, and J. Wardle Psychological and Behavioural Impact of Genetic Testing Smokers for Lung Cancer Risk: A Phase II Exploratory Trial J Health Psychol, May 1, 2008; 13(4): 481 - 494. [Abstract] [PDF]
|
|
|
|
 |
|
 S. P. Moffett, J. I. Oakley, J. A. Cauley, L. Y. Lui, K. E. Ensrud, B. C. Taylor, T. A. Hillier, M. C. Hochberg, J. Li, S. Cayabyab, et al. Osteoprotegerin Lys3Asn Polymorphism and the Risk of Fracture in Older Women J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 2002 - 2008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Kelemen, T. A. Sellers, J. M. Schildkraut, J. M. Cunningham, R. A. Vierkant, V. S. Pankratz, Z. S. Fredericksen, M. K. Gadre, D. N. Rider, M. Liebow, et al. Genetic Variation in the One-Carbon Transfer Pathway and Ovarian Cancer Risk Cancer Res., April 1, 2008; 68(7): 2498 - 2506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Roth Perspective on the future use of genomics in exercise prescription J Appl Physiol, April 1, 2008; 104(4): 1243 - 1245. [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. White, D. Li, Z. Nurgalieva, and H. B. El-Serag Genetic Variants of Glutathione S-Transferase as Possible Risk Factors for Hepatocellular Carcinoma: A HuGE Systematic Review and Meta-Analysis Am. J. Epidemiol., February 15, 2008; 167(4): 377 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Williams and J. P. Folland Similarity of polygenic profiles limits the potential for elite human physical performance J. Physiol., January 1, 2008; 586(1): 113 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Torkamani and N. J. Schork Accurate prediction of deleterious protein kinase polymorphisms Bioinformatics, November 1, 2007; 23(21): 2918 - 2925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Authors/Task Force Members, I. Graham, D. Atar, K. Borch-Johnsen, G. Boysen, G. Burell, R. Cifkova, J. Dallongeville, G. De Backer, S. Ebrahim, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts) Eur. Heart J., October 1, 2007; 28(19): 2375 - 2414. [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Wray, M. E. Goddard, and P. M. Visscher Prediction of individual genetic risk to disease from genome-wide association studies Genome Res., October 1, 2007; 17(10): 1520 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Patsopoulos, A. Tatsioni, and J. P. A. Ioannidis Claims of Sex Differences: An Empirical Assessment in Genetic Associations JAMA, August 22, 2007; 298(8): 880 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Ntzani, E. C. Rizos, and J. P. A. Ioannidis Genetic Effects versus Bias for Candidate Polymorphisms in Myocardial Infarction: Case Study and Overview of Large-Scale Evidence Am. J. Epidemiol., May 1, 2007; 165(9): 973 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J Khoury, J. Little, M. Gwinn, and J. P. Ioannidis On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies Int. J. Epidemiol., April 1, 2007; 36(2): 439 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hemminki and J. L. Bermejo Constraints for genetic association studies imposed by attributable fraction and familial risk Carcinogenesis, March 1, 2007; 28(3): 648 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Peng and M. Kimmel Simulations Provide Support for the Common Disease-Common Variant Hypothesis Genetics, February 1, 2007; 175(2): 763 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Humphries, J. A. Cooper, P. J. Talmud, and G. J. Miller Candidate Gene Genotypes, Along with Conventional Risk Factor Assessment, Improve Estimation of Coronary Heart Disease Risk in Healthy UK Men Clin. Chem., January 1, 2007; 53(1): 8 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. A. Ioannidis, T. A. Trikalinos, and M. J. Khoury Implications of Small Effect Sizes of Individual Genetic Variants on the Design and Interpretation of Genetic Association Studies of Complex Diseases Am. J. Epidemiol., October 1, 2006; 164(7): 609 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Groves, E. Zeggini, J. Minton, T. M. Frayling, M. N. Weedon, N. W. Rayner, G. A. Hitman, M. Walker, S. Wiltshire, A. T. Hattersley, et al. Association Analysis of 6,736 U.K. Subjects Provides Replication and Confirms TCF7L2 as a Type 2 Diabetes Susceptibility Gene With a Substantial Effect on Individual Risk Diabetes, September 1, 2006; 55(9): 2640 - 2644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. MOONESINGHE A refinement to 'how many genes underlie the occurrence of common complex diseases in the population?' Int. J. Epidemiol., April 1, 2006; 35(2): 497 - 497. [Full Text] [PDF]
|
|
|
|
|
|
J. PEEDICAYIL Genes underlying common complex diseases Int. J. Epidemiol., April 1, 2006; 35(2): 490 - 491. [Full Text] [PDF]
|
|