Common vs. rare allele hypotheses for complex diseases

https://doi.org/10.1016/j.gde.2009.04.010Get rights and content

There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The ‘Common Disease, Common Variant (CDCV)’ hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low ‘penetrance’ (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common diseases. The ‘Common Disease, Rare Variant (CDRV)’ hypothesis, on the contrary, argues that multiple rare DNA sequence variations, each with relatively high penetrance, are the major contributors to genetic susceptibility to common diseases. Both hypotheses have their place in current research efforts.

Section snippets

A brief history of the debate

Debates concerning precisely how genetic variations contribute to phenotypic expression have been at the heart of a great deal of biomedical research for more than a century. In fact, one of the most contentious yet insightful of these debates occurred at the turn of the 20th century and was rooted in positions championed by two opposing intellectual camps. The ‘Mendelians,’ in the form of William Bateson, Hugo de Vries, and others, focused on discrete gene-based units of inheritance and

Background evidence

The evidence that multiple rare variations might be contributing to human phenotypic variation is consistent with some early in-depth sequencing and re-sequencing studies of human genic variation. For example, studies by Nickerson and colleagues in the late 1990s on the lipoprotein lipase (LpL) gene suggested that a number of naturally occurring variations, both common and rare, are likely to influence LpL function. LpL is a gene known to be a contributor to cholesterol levels and ultimately,

Verifying findings associated with each hypothesis

In order to substantiate claims about the role of either specific common or rare variations in disease, some form of validation of an initial finding implicating those variations is in order. For common variations implicated in GWA and candidate gene association studies, the sine qua non of validation is replication of the association in an independent population or sample of individuals than that used in the initial study [33]. However, replication studies of associations involving rare

Conclusion

The contemporary CDCV vs. CDRV debate is, as noted, not only rooted in historical debates about the nature of phenotypic variation, but also implicates different strategies for identifying genetic variations that predispose individuals to a disease. It is safe to say, however, that strategies for uncovering common and rare variations should be pursued for any disease phenotype, and that the CDCV/CDRV debate should be seen as not an ‘either/or’ debate, but rather as a debate about the degree to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors benefited from the following research grants: The National Institute on Aging Longevity Consortium (U19 AG023122-01); The NIMH-funded Genetic Association Information Network Study of Bipolar Disorder (R01 MH078151-01A1); National Institutes of Health grants: N01 MH22005, U01 DA024417-01, and P50 MH081755-01; and the Scripps Translational Sciences Institute Clinical Translational Science Award (U54 RR0252204-01). Additional funding came from Scripps Genomic Medicine and the Price

References (49)

  • R.P. Lifton

    Molecular genetics of human blood pressure variation

    Science

    (1996)
  • W. Bodmer et al.

    Common and rare variants in multifactorial susceptibility to common diseases

    Nat Genet

    (2008)
  • D.A. Nickerson et al.

    DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene

    Nat Genet

    (1998)
  • D.C. Crawford et al.

    Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations

    Am J Hum Genet

    (2004)
  • C. Szabo et al.

    The breast cancer information core: database design, structure, and scope

    Hum Mutat

    (2000)
  • K.A. Frazer et al.

    A second generation human haplotype map of over 3.1 million SNPs

    Nature

    (2007)
  • T.A. Manolio et al.

    A HapMap harvest of insights into the genetics of common disease

    J Clin Invest

    (2008)
  • B. Maher

    Personal genomes: the case of the missing heritability

    Nature

    (2008)
  • N.J. Schork et al.

    DNA sequence-based phenotypic association analysis

    Adv Genet

    (2008)
  • E.E. Eichler et al.

    Completing the map of human genetic variation

    Nature

    (2007)
  • T. Walsh et al.

    Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

    Science

    (2008)
  • E.H. Cook et al.

    Copy-number variations associated with neuropsychiatric conditions

    Nature

    (2008)
  • S. Levy et al.

    The diploid genome sequence of an individual human

    PLoS Biol

    (2007)
  • D.A. Wheeler et al.

    The complete genome of an individual by massively parallel DNA sequencing

    Nature

    (2008)
  • Cited by (0)

    View full text