Trends in Genetics
Volume 18, Issue 1, 1 January 2002, Pages 19-24
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Linkage disequilibrium and the mapping of complex human traits

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Abstract

The potential value of haplotypes defined by several single nucleotide polymorphisms has attracted recent interest. With sufficient linkage disequilibrium (LD), haplotypes could be used in association studies to map common alleles that might influence the susceptibility to common diseases, as well as for reconstructing the evolution of the genome. It has been proposed that a globally useful resource need only be based on high frequency variants, identified from a few modest samples. Rapid progress has been made in quantifying the pattern of human LD and haplotypes defined by such common variants within and among populations. However, the quality and utility of the proposed LD-based resource could be seriously compromised if important sampling and analytical factors are overlooked in its design. The LD map should be based on adequately justified criteria defined by sound population genetic principles.

Section snippets

LD in the human genome

Population genetics theory describes the way mutation, gene conversion, recombination, natural selection and the demographic structure of human populations affect patterns of LD. These forces vary along the genome and are generated by highly stochastic (probablistic) processes, so there is currently no a priori way to predict the LD pattern in any particular genomic region, and it must be assessed empirically in appropriately chosen samples.

Sample size effects

D′∣ is biased upward inversely with sample size. In the Reich et al. study, the Yoruban samples were twice the number of the European samples, and if only half the Yoruban data are used, their mean LD patterns are closer to the Europeans (Fig. 2). This effect is increased by using a quarter of the Yoruban data (not shown). If such a sample is to be used to design a global mapping panel, it should be large enough that the observed LD structure is not an artifact of small sample size.

LD and haplotypes

We have so far used the Reich et al. data to raise sampling issues regarding SNP choice, and we now illustrate the effects of defining haplotypes from a subset of common SNPs in those data. Reich et al. suggest that haplotypes occur in roughly 50-kb ‘blocks’ that can be characterized by only one or two markers. We extracted five-site haplotypes for individuals in the Reich et al. data who have two unambiguous haplotypes (this avoids issues of statistically inferring probable phasing of the two

Missed opportunities?

The finding in the European samples that there is substantial LD (measured by D′) over 60 kb raises hopes that widely separated SNPs might capture the haplotype variation across the genome. But omitting polymorphic sites collapses existing haplotypes into a restricted number of detectable haplotype classes. If we were to type only the two SNPs 40-kb apart, that is, if we had believed LD in the whole region could actually be captured by the two spanning sites, Table 1 shows that we would miss

Conclusion: a 93% haplotype map or a 7% solution?

An accurate large-scale survey of human single nucleotide polymorphisms would be an exciting and valuable tool so it is important to design it carefully. We have raised several purely genetic issues related to resource design. A primary justification for the proposed tool is the CDCV model (Box 1), but this is not obviously correct. If alleles with large effects on disease risk turn out to be rare and geographically localized, rather than common and global, a haplotype map based on common SNPs

Acknowledgements

We acknowledge NIH/NHLBI grant HL58239.

References (34)

  • R. Nielsen

    Estimation of population parameters and recombination rates from single nucleotide polymorphisms

    Genetics

    (2000)
  • J. Jaruzelska

    Spatial and temporal distribution of the neutral polymorphisms in the last ZFX intron: analysis of the haplotype structure and genealogy

    Genetics

    (1999)
  • L.L. Cavalli-Sforza

    The History and Geography of Human Genes

    (1994)
  • A. Collins

    Genetic epidemiology of single-nucleotide polymorphisms

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • C. Lonjou

    Allelic association between marker loci

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • M.F. Moffatt

    Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus

    Hum. Mol. Genet.

    (2000)
  • D. Reich

    Linkage disequilibrium in the human genome

    Nature

    (2001)
  • Cited by (0)

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