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GENETIC
EPIDEMIOLOGY
M.Tevfik DORAK
Genetic
Epidemiology PowerPoint Presentation (PPT)
Statistical Analysis of Genetic Associations
Classical epidemiology deals with disease patterns and
factors associated with causation of diseases with the ultimate aim of
preventing the disease. Molecular epidemiologic studies measure exposure to
specific substances (DNA adducts) and early biological response (somatic
mutations), evaluate host characteristics (genotype and phenotype) mediating
response to external agents, and use markers of a specific effect (like gene
expression) to refine disease categories (such as heterogeneity, etiology and
prognosis). Genetic epidemiology
overlaps with molecular epidemiology. It is the epidemiological evaluation of
the role of inherited causes of disease in families and in populations; it aims
to detect the inheritance pattern of a particular disease, localize the gene
and find a marker associated with disease susceptibility. Gene-gene and
gene-environment interactions are also studied in genetic epidemiology of a
disease. The most widely accepted definition of genetic epidemiology is by
Morton: ‘a science which deals with the etiology, distribution, and control of
disease in groups of relatives and with inherited causes of disease in
populations’ (Morton
NE, 1982).
Genetic
epidemiology was born in the 1960s as the merger of
population/statistical/mathematical genetics
and classical/molecular epidemiology. The pioneers include Newton
Morton, Douglas
Falconer, Robert
C Elston, Elizabeth A
Thompson and Neil
Risch.
The steps, a genetic
epidemiologic research follows,
are:
1. Establishing that there is a genetic
component to the disorder.
2. Establishing the relative size of that
genetic effect in relation to other sources of variation in disease risk
(environmental effects such as intrauterine environment, physical and chemical
effects as well as behavioral and social aspects).
3. Identifying the gene(s) responsible for
the genetic component.
All of these can be achieved either in family studies (segregation, linkage,
association) or in population
studies (association).
General methods employed in genetic epidemiology:
* Genetic risk
studies: What is the contribution of genetics as opposed to environment to
the trait? Requires family-based, twin/adoption or migrant studies.
* Segregation analyses: What does
the genetic component look like (oligogenic 'few genes each with a moderate
effect', polygenic 'many genes each with a small effect', etc)? What is the
model of transmission of the genetic trait? Segregation analysis requires
multigeneration family trees preferably with more than one affected member.
* Linkage studies: What is the
location of the disease gene(s)? Linkage studies screen the whole genome and
use parametric or nonparametric methods such as allele sharing methods
{affected sibling-pairs method} with no assumptions on the mode of inheritance,
penetrance or disease allele frequency (the parameters). The underlying
principle of linkage studies is the cosegregation of two genes (one of which is
the disease locus).
* Association studies: What is the
allele associated with the disease susceptibility? The principle is the
coexistence of the same marker on the same chromosome in affected individuals
(due to linkage disequilibrium). Association studies may be family-based (transmission
/ disequilibrium test - TDT;
also called transmission distortion test) or population-based. Alleles,
haplotypes or evolutionary-based haplotype groups may be used in association studies
(Clark,
2004; Tzeng,
2005). More recently, genome-wide association studies (GWAS) have become
possible (Clark, 2005; the WTCCC
GWAS (PDF)
and a list of recent GWASs in OEGE).
The samples needed for these studies may be nuclear families (index case and parents), affected relative pairs (sibs, cousins, any two members of the family), extended pedigrees, twins (monozygotic and dizygotic) or unrelated population samples.
Genetic epidemiologic approach
When the question is whether a disease has a genetic component, the detection and estimation of familial aggregation (e.g., higher occurrence rates in siblings or offspring) is the first step in the approach. This may already be known from descriptive epidemiology studies. Results of observational studies on siblings, parent-offspring concordance, twins, adoptees and even migrants may suggest a genetic component in the etiology of a disease or trait. Familial aggregation of a trait is a necessary but not sufficient condition to infer the importance of genetic susceptibility, because environmental and cultural influences can also aggregate in families, leading to family clustering and excess familial risk. Similar environment may be the reason for familial aggregation. With rising divorce rates, study of recurrence risk in half-siblings is another powerful method to test for parent-specific events. In an application of this method, multiple sclerosis appeared to have a genetic basis transmitted more from mothers than fathers (Ebers, 2004).
Familial aggregation for a disease is measured by the relative recurrence risk (RRR) or familial risk ratios (FRRs). These are quantities denoted by lR, where R denotes a relationship (S=sib, O=offspring, DZ= dizygotic twin, C=cousin etc), and whose values are the risks of relatives of type R of affected individuals being themselves affected, divided by the population prevalence. Examination of relative recurrence risk values for various classes of relatives can potentially suggest a polygenic background and epistasis (Risch, 1990a; 2001). The estimation of ls is prone to ascertainment bias and should be performed with great care (Chakraborty, 1987;