Genetics of Large Populations and Association Studies

Pauline Hélène Garnier‐Géré, INRA – UMR1202 Biodiversity Genes & Communities, Cestas, France
Lounès Chikhi, Université Paul Sabatier, Toulouse, France

Published online: March 2008

DOI: 10.1002/9780470015902.a0005446.pub2

Association studies aim to discover the genetic basis of genetic diseases or drug responses through the comparison of unrelated affected and nonaffected individuals in large populations assumed to be at Hardy–Weinberg equilibrium (HWE). The HWE principle and the main causes of departures are first described with a focus on population stratification (Wahlund effect), which is one of the major problems in association studies. Recent statistical methods developed to detect and control for it are briefly reviewed.

Keywords: Hardy–Weinberg equilibrium; Wahlund effect; population stratification; linkage disequilibrium; association studies

Figure 1. Hardy–Weinberg (HW) equilibrium and Wahlund effect. The solid curve represents the proportion of heterozygotes in a population at HW equilibrium for a biallelic locus, where p1 is the allelic frequency of one of the two alleles. The population P is subdivided in two subpopulations or strata, P1 and P2, which are both at HW equilibrium for different allelic frequencies (p1=0.2 and 0.6, respectively). P1 and P2 are both on the solid curve, whereas P is necessarily below, indicating that the Wahlund effect leads to a heterozygote deficit.
close
 References
    Abecasis GR, Ghosh D and Nichols TE (2005) Linkage disequilibrium: ancient history drives the new genetics. Human Heredity 59: 118–124.
    Abecasis GR, Noguchi E, Heinzmann A et al. (2001) Extent and distribution of linkage disequilibrium in three genomic regions. American Journal of Human Genetics 68: 191–197.
    Altshuler D, Brooks LD, Chakravarti A et al. (2005) A haplotype map of the human genome. Nature 437: 1299–1320.
    Emahazion T, Feuk L, Jobs M et al. (2001) SNP association studies in Alzheimer's disease highlight problems for complex disease analysis. Trends in Genetics 17(7): 407–413.
    Freedman ML, Reich D, Penney KL et al. (2004) Assessing the impact of population stratification on genetic association studies. Nature Genetics 36: 388–393.
    Goldstein DB (2001) Islands of linkage disequilibrium. Nature Genetics 29: 109–111.
    book Hedrick PW (2000) Genetics of Populations, 2nd edn. Boston, MA: Jones and Bartlett Publishers.
    Hirschhorn JN and Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nature Reviews Genetics 6: 95–108.
    Jeffreys AJ, Kauppi L and Neumann R (2001) Intensely punctuate meiotic recombination in the class II region of the major histocompatibility complex. Nature Genetics 29: 217–222.
    Kruglyak L (1999) Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genetics 22: 139–144.
    Laird NM and Lange C (2006) Family based designs in the age of large-scale gene-association studies. Nature Reviews Genetics 7: 385–394.
    Long AD and Langley CH (1999) The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Research 9: 720–731.
    Lu X, Niu T and Liu JS (2003) Haplotype information and linkage disequilibrium mapping for single nucleotide polymorphisms. Genome Research 13: 2112–2117.
    Marchini J, Cardon LR, Phillips MS et al. (2004) The effects of human population structure on large genetic association studies. Nature Genetics 36: 512–517.
    Patterson N, Price AL and Reich D (2006) Population structure and eigenanalysis. PLoS Genetics 2(12): 2074–2093.
    Price AL, Patterson NJ, Plenge RM et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38(8): 904–909.
    Pritchard JK and Rosenberg NA (1999) Use of unlinked genetic markers to detect population stratification in association studies. American Journal of Human Genetics 65: 220–228.
    Pritchard JK, Stephens M, Rosenberg NA and Donnelly P (2000) Association mapping in structured populations. American Journal of Human Genetics 67: 170–181.
    Reich DE, Cargill M, Bolk S et al. (2001) Linkage disequilibrium in the human genome. Nature 411: 199–204.
    Reich DE and Goldstein DB (2001) Detecting association in a case–control study while correcting for population stratification. Genetic Epidemiology 20: 4–16.
    Risch N and Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273: 1516–1517.
    Setakis E, Stirnadel H and Balding DJ (2006) Logistic regression protects against population structure in genetic association studies. Genome Research 16: 290–296.
    book Sham P (1998) Statistics in Human Genetics. Arnold Applications of Statistics. New York, NY: Oxford University Press.
    Spielman RS, McGinnis RE and Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). American Journal of Human Genetics 52: 506–516.
    Stumpf MP and Goldstein DG (2003) Demography, recombination hotspot intensity, and the block-structure of linkage disequilibrium. Current Biology 13: 1–8.
    Wright S (1951) The genetical structure of populations. Annals of Eugenics 15: 323–354.
    Yu JM, Pressoir G, Briggs WH et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics 38: 203–208.
 Further Reading
    Balding DJ (2006) A tutorial on statistical methods for population association studies. Nature Reviews Genetics 7: 781–791.
    book Crow JF and Kimura M (1970) An Introduction to Population Genetics Theory. New York: Harper and Row.
    Goldstein DB and Weale ME (2001) Population genomics: linkage disequilibrium holds the key. Current Biology 11: 576–579.
    book Hartl DL and Clark AG (1989) Principles of Population Genetics, 2nd edn. Sunderland, MA: Sinauer Associates.
    book Liu BH (1998) Statistical Genomics. Linkage, Mapping, and QTL Analyses. Boca Raton, FL: CRC Press.
    Marchini J, Donnelly P and Cardon LR (2005) Genome-wide strategies for detecting multiple loci that influence complex diseases. Nature Genetics 37: 413–417.
    Nei M and Li W-H (1973) Linkage disequilibrium in subdivided populations. Genetics 75: 213–219.
    Pritchard JK and Przeworski M (2001) Linkage disequilibrium in humans: models and data. American Journal of Human Genetics 69: 1–14.
    Slatkin M (1994) Linkage disequilibrium in growing and stable populations. Genetics 137: 331–336.
    Stephens JC, Briscoe D and O'Brien SJ (1994) Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. American Journal of Human Genetics 55: 809–824.
    book Strachan T and Read AP (1996) Human Molecular Genetics. Oxford, UK: BIOS Scientific Publishers.
    book Weir BS (1996) Genetic Data Analysis, vol. 2. Sunderland, MA: Sinauer Associates.

Related Sub-Topics:

Population Structure and Genetics | Linkage Analysis | Statistical Methodology in Genetics | Gene Mapping by Disease Association
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Genetics of Large Populations and Association Studies
 
How to Cite close
Garnier‐Géré, Pauline Hélène, and Chikhi, Lounès(Mar 2008) Genetics of Large Populations and Association Studies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005446.pub2]