Genetics of common disorders

The genetic contribution to disease varies; some disorders are
entirely environmental and others are wholly genetic. Many
common disorders, however, have an appreciable genetic
contribution but do not follow simple patterns of inheritance
within a family. The terms multifactorial or polygenic
inheritance have been used to describe the aetiology of these
disorders. The positional cloning of multifactorial disease genes
presents a major challenge in human genetics.

Multifactorial inheritance

The concept of multifactorial inheritance implies that a disease
is caused by the interaction of several adverse genetic and
environmental factors. The liability of a population to a
particular disease follows a normal distribution curve, most
people showing only moderate susceptibility and remaining
unaffected. Only when a certain threshold of liability is
exceeded is the disorder manifest. Relatives of an affected
person will show a shift in liability, with a greater proportion of
them being beyond the threshold. Familial clustering of a
particular disorder may therefore occur. Genetic susceptibility
to common disorders is likely to be due to sequence variation
in a number of genes, each of which has a small effect, unlike
the pathogenic mutations seen in mendelian disorders. These
variations will also be seen in the general population and it is
only in combination with other genetic variations that disease
susceptibility becomes manifest.

molecular genetics of the complex multifactorial diseases

Unravelling the molecular genetics of the complex
multifactorial diseases is much more difficult than for single
gene disorders. Nevertheless, this is an important task as these
diseases account for the great majority of morbidity and
mortality in developed countries. Approaches to multifactorial
disorders include the identification of disease associations in
the general population, linkage analysis in affected families,
and the study of animal models. Identification of genes causing
the familial cases of diseases that are usually sporadic, such as
Alzheimer disease and motor neurone disease, may give
insights into the pathogenesis of the more common sporadic
forms of the disease. In the future, understanding genetic
susceptibility may enable screening for, and prevention of,
common diseases as well as identifying people likely to respond
to particular drug regimes.

Risk of recurrence

The risk of recurrence for a multifactorial disorder within a
family is generally low and mainly affects first degree relatives.
In many conditions family studies have reported the rate with
which relatives of the index case have been affected. This allows
empirical values for risk of recurrence to be calculated, which
can be used in genetic counselling. Risks are mainly increased
for first degree relatives. Second degree relatives have a slight
increase in risk only and third degree relatives usually have the
same risk as the general population. The severity of the
disorder and the number of affected individuals in the family
also affect recurrence risk. The recurrence risk for bilateral
cleft lip and palate is higher than the recurrence risk for cleft
lip alone, and the recurrence risk for neural tube defect is 4%
after one affected child, but 12% after two. Some conditions
are more common in one sex than the other. In these disorders
the risk of recurrence is higher if the disorder has affected the
less frequently affected sex. As with the other examples, the
greater genetic susceptibility in the index case confers a higher
risk to relatives. A rational approach to preventing
multifactorial disease is to modify known environmental
triggers in genetically susceptible subjects. Folic acid
supplementation in pregnancies at increased risk of neural
tube defects and modifying diet and smoking habits in
coronary heart disease are examples of effective intervention,
but this approach is not currently possible for many disorders.

Heritability

The heritability of a variable trait or disorder reflects the
proportion of the variation that is due to genetic factors. The
level of this genetic contribution to the aetiology of a disorder
can be calculated from the disease incidence in the general
population and that in relatives of an affected person.
Disorders with a greater genetic contribution have higher
heritability, and hence, higher risks of recurrence.

important disorders

Several important disorders occur more commonly than
expected in subjects with particular HLA phenotypes, which
implies that certain HLA determinants may affect disease
susceptibility. Awareness of such associations may be helpful
in counselling. For example, ankylosing spondylitis, which has
an overall risk of recurrence of 4% in siblings, shows a strong
association with HLA-B27, and 95% of affected people are
positive for this antigen. The risk to their first degree
relatives is increased to 9% for those who are also positive for
HLA-B27 but reduced to less than 1% for those who are
negative.

Genetic association

Genetic association, which may imply a causal relation, is
different from genetic linkage, which occurs when two gene loci
are physically close together on the chromosome. A disease gene,
located near the HLA complex of genes on chromosome 6, will
be linked to a particular HLA haplotype within a given affected
family but will not necessarily be associated with the same HLA
antigens in unrelated affected people. HLA typing can be used
to predict disease by establishing the linked HLA haplotype
within a given family.