Commentary: Rare alleles, modest genetic effects and the need for collaboration
| Autor: | T Manolio, Harry Campbell |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
education.field_of_study Epidemiology Population Genome-wide association study General Medicine Disease Biology Penetrance Pedigree Evolutionary biology Genetic variation Humans Female Genetic Predisposition to Disease Genetic Testing Cooperative Behavior Allele education Alleles Genetic association Common disease-common variant |
| Zdroj: | International Journal of Epidemiology. 36:445-448 |
| ISSN: | 1464-3685 0300-5771 |
| DOI: | 10.1093/ije/dym055 |
| Popis: | of the complex issues facing those trying to identify genetic variants underlying common complex disease. They focus on the common disease—common variant model where effect sizes associated with individual genetic variants are small. Undoubtedly this will be the case for most, but not all, variants. An L-shaped or exponential distribution of mutation effect sizes has wide support 2–4 with many variants with small effects, a smaller number with intermediate effects and relatively few with large effects. It could be argued that the genetic variants related to human disease that have been identified to date primarily reflect the study designs used to identify them. Linkage studies conducted among families with multiple cases of disease were successful in identifying highly penetrant variants with large effects. Association studies conducted in general population samples using common genetic markers typically find low penetrance variants with (very) small effects, as noted by Khoury. This is not unexpected given that these common genetic variants are ancient and will have been subject to some selective pressure over time. 3 We can predict that re-sequencing studies in the near future which study rarer variants (say 0.05–5%) will identify many variants of intermediate effect associated with common complex disease. This paradigm shift has already begun with the seminal work of Cohen, who compared non-synonymous sequence variations in individuals at the extremes of the population distribution of LDL-cholesterol levels, and determined that a significant fraction of genetic variance is due to multiple alleles with intermediate effects that are present at low frequencies (0.05–5%) in the population, particularly persons of African ancestry. 5 Until many such studies are reported it will be premature to decide on the relative importance of the common variant—common disease model and the alternative rare variant—common disease model which states that disease susceptibility to common diseases is the result of multiple low frequency/rare variants with larger phenotypic effects. As Cohen notes, although individually rare, these variants may be collectively common in the population. This has important consequences since the issues of causal inference and clinical application, described well by Khoury, maybe somewhat different for these variants. Our view of the genetic contribution to common complex disease is becoming clearer but is still biased as it is highly determined by available genetic technology and its cost. 6 Nevertheless, the questions raised by Khoury with respect to the common variants currently employed in genetic association studies are important to consider. The most immediate questions are perhaps how to interpret the findings of the increasing number of genome-wide association (GWA) studies which are now being conducted and how this global research effort could be most efficiently marshalled. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|