Common vs. rare allele hypotheses for complex diseases
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
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