ViewpointAssociation studies of genetic polymorphisms and complex disease
Section snippets
What is a population association study?
Mapping a disease locus—ie, the identification of a chromosome of a gene causing a disease—is the major task of molecular genetics. However, the more common inherited disorders are difficult to study, because a combination of various genes and different environmental factors is often involved. Many complex diseases are thought to be inherited since they tend to run in families, but they do not show typical mendelian pedigree patterns. These non-mendelian diseases may depend on two or more
Population association study for the clinical investigator
Examination of several reports, and talks by clinical investigators about studies in which this approach was used, persuaded us that, although geneticists have defined the limitations of this approach, these aspects have been only in part appreciated by clinical investigators. Furthermore, we think that non-manifest assumptions implicitly guide the clinical investigator in choosing the candidate allele and the polymorphism association study approach to identify biomarkers of inherited
Example
The angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism is one of the most appealing polymorphisms in susceptibility to cardiovascular disease. For the period January, 1995, to October, 1996, a Medline search identified 145 studies5 with a total of almost 50 000 individuals-an enormous clinical and scientific effort, and a very expensive one.
Starting from the observation that this polymorphism accounts for half the variance of serum ACE concentrations,6 the D allele was
What are the risks of population association studies?
The implicit sequence that constitutes the working hypothesis formulated by the clinical investigator when the polymorphism association approach is used was summarised above as: q gene → z allele → y phenomenon → x disease.
The z allele is often chosen at random, and thus it is not known whether it is neutral or non-neutral in relation to the disease or the intermediate phenotype. Generally, the complexity of this algorithm is not clear in the mind of the clinician who is interpreting the
References (13)
Associations of disease with genetic markers: déjà vu all over again
Am J Med Genet (Neuropsych Genet)
(1993)- et al.
- et al.
DNA polymorphisms and linkage disequilibrium in the angiotensinogen gene
Hum Genet
(1996) - et al.
The future of genetic studies of complex human diseases
Science
(1996) - et al.
The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk
J Hypertens
(1997) - et al.
An insertion/deletion polymorphism in the angiotensin 1 converting enzyme gene accounting for half the variance of serum enzyme levels
J Clin Invest
(1990)
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Association of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism with the Risk of Atherosclerosis
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