Abstract
The study of the genetics of complex traits is made complicated by the fact that the traits themselves are influenced by an interplay of many genes with many environmental factors. In this chapter the historical concepts of quantitative genetics, including additive variance and heritability, will be developed to underscore how important it is to understand that the root of the problem is to explain how genes contribute to the variance in a trait. With molecular genetic markers, such as SNPs, it is possible to test whether there are differences in the measured phenotype among the genotypes at the genetic marker, and this serves as a crude test of association. Many interesting challenges arise when such a test is expanded to 1 million markers spanning the entire chromosome, a design known as a genome-wide association study (GWAS). Complications due to population stratification, admixture, genotype x environment interaction, epistasis, and rare alleles are all considered. Methods that test association by use of excess of allele sharing in siblings (affected sib methods) or other relatives, or by excess cotransmission of alleles and a disease state (transmission disequilibrium test) have their own set of advantages and disadvantages. The chapter closes with some considerations of why the powerful methods presented here nevertheless leave much of the genetic variance in complex traits unexplained.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Altshuler D, Daly MJ, Lander ES (2008) Genetic mapping in human disease. Science 322:881–888
Cheung VG, Bruzel A, Burdick JT, Morley M, Devlin JL, Spielman RS (2008) Monozygotic twins reveal germline contribution to allelic expression differences. Am J Hum Genet 82:1357–1360
Cooper GM, Johnson JA, Langaee T Y, Feng H, Stanaway IB, Schwarz UI, Ritchie MD, Stein CM, Roden DM, Smith JD, Veenstra DL, Rettie AE, Rieder MJ (2008) A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 112:1022–1027
Detera-Wadleigh SD, Badner JA, Berrettini WH et al (1999) A high-density genome scan detects evidence for a bipolardisorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 96:5604–5609
Dimas AS, Stranger BE, Beazley C, Finn RD, Ingle CE, Forrest MS, Ritchie ME, Deloukas P, Tavaré S, Dermitzakis ET (2008) Modifier effects between regulatory and protein—coding variation. PLoS Genet 4:e1000244
Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4th edn. Longman Group Ltd, London
Fisher RA (1918) The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb 52:399–433
Guan Y, Stephens M (2008) Practical issues in imputation-based association mapping. PLoS Genet 4(12):e1000279
Klein RJ, Zeiss C, Chew E Y, Tsai J Y, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389
Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA (2008) MYH9 is a major-effect risk gene for focal segmental glom-erulosclerosis. Nat Genet 40:1175–1184
Marchini J, Howie B (2008) Comparing algorithms for genotype imputation. Am J Hum Genet 83:535–539
Menozzi P, Piazza A, Cavalli-Sforza L (1978) Synthetic maps of human gene frequencies in Europeans. Science 201:786–792
Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR, Stephens M, Bustamante CD (2008) Genes mirror geography within Europe. Nature 456:98–101
Ohta T, Kimura M (1969) Linkage disequilibrium due to random genetic drift. Genet Res 13:47–55
Poulsen P, Vaag A (2003) The impact of genes and pre- and postnatal environment on the metabolic syndrome. Evidence from twin studies. Panminerva Med 45:109–115
Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959
Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on tran-scriptional regulation and warfarin dose. N Engl J Med 352:2285–2293
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517
Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, Xie X, Byrne EH, McCarroll SA, Gaudet R, Schaffner SF, Lander ES, The International HapMap Consortium (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449:913–918 [Abstract] [PDF]
Schaid DJ, Olson JM, Gauderman WJ, Elston RC (2003) Regression models for linkage: issues of traits, covariates, heterogeneity, and interaction. Hum Hered 55:86–96
Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516
Sved JA (1968) The stability of linked systems of loci with a small population size. Genetics 59:543–563
Tang H, Coram M, Wang P, Zhu X, Risch N (2006) Reconstructing genetic ancestry blocks in admixed individuals. Am J Hum Genet 79:1–12
Wang Y, Mi J, Shan XY, Wang QJ, Ge KY (2007) Is China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China. Int J Obes 31:177–188
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
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Clark, A.G. (2010). Formal Genetics of Humans: Multifactorial Inheritance and Common Diseases. In: Speicher, M.R., Motulsky, A.G., Antonarakis, S.E. (eds) Vogel and Motulsky's Human Genetics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-37654-5_9
Download citation
DOI: https://doi.org/10.1007/978-3-540-37654-5_9
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-37653-8
Online ISBN: 978-3-540-37654-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)