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.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia due to 21-hydroxylase
deficiency shows both linkage and association with
histocompatibility antigens. The 21-hydroxylase gene lies within
the HLA gene cluster and is therefore linked to the HLA
haplotype. In addition, the salt-losing form of 21-hydroxylase
deficiency is associated with HLA-Bw47 antigen. This
combination of linkage and association is known as linkage
disequilibrium and results in certain alleles at neighbouring
loci occurring together more often than would be expected by
chance.

Twins

Twins share a common intrauterine environment, but
though monozygous twins are genetically identical with respect
to their inherited nuclear DNA, dizygous twins are no more
alike than any other pair of siblings, sharing, on average, half
their genes. This provides the basis for studying twins to
determine the genetic contribution in various disorders, by
comparing the rates of concordance or discordance for a
particular trait between pairs of monozygous and dizygous
twins. The rate of concordance in monozygous twins is high for
disorders in which genetic predisposition plays a major part in
the aetiology of the disease. The phenotypic variability of
genetic traits can be studied in monozygous twins, and the
effect of a shared intrauterine environment may be studied in
dizygous twins.

Twins

Twins may be derived from a single egg (monozygous,
identical) or two separate eggs (dizygous, fraternal).
Examination of the placenta and membranes may help to
distinguish between monozygous and dizygous twins but is not
completely reliable. Monozygosity, resulting in twins of the
same sex who look alike, can be confirmed by investigating
inherited characteristics such as blood group markers or DNA
polymorphisms (fingerprinting).

genetic predisposition

A genetic predisposition is well recognised in both type I
insulin dependent diabetes (IDDM) and type II non-insulin
dependent diabetes (NIDDM). Maturity onset diabetes of the
young (MODY) is a specific form of non-insulin dependent
diabetes that follows autosomal dominant inheritance and has
been shown to be due to mutations in a number of different
genes. Clinical diabetes or impaired glucose tolerance also
occurs in several genetic syndromes, for example,
haemochromatosis, Friedreich ataxia, and Wolfram
syndrome (diabetes mellitus, optic atrophy, diabetes insipidus
and deafness). Only rarely is diabetes caused by the secretion
of an abnormal insulin molecule.

IDDM

IDDM affects about 3 per 1000 of the population in the
UK and is a T cell dependent autoimmune disease. Genetic
predisposition is important, but only 30% of monozygous
twins are concordant for the disease and this indicates that
environmental factors (such as triggering viral infections)
are also involved. About 60% of the genetic susceptibility to
IDDM is likely to be due to genes in the HLA region. The
overall risk to siblings is about 6%. This figure rises to 16% for
HLA identical siblings and falls to 1% if they have no shared
haplotype. An association with DR3 and DR4 class II antigens is
well documented, with 95% of insulin dependent diabetics
having one or both antigens, compared to 50–60% of the
normal population. As most people with DR3 or DR4 class II
antigens do not develop diabetes, these antigens are unlikely
to be the primary susceptibility determinants. Better definition
of susceptible genotypes is becoming possible as subgroups of
DR3 and DR4 serotypes are defined by molecular analysis.
For example, low risk HLA haplotypes that confer protection
always have aspartic acid at position 57 of the DQB1 allele.
High risk haplotypes have a different amino acid at this
position and homozygosity for non-aspartic acid residues is
found much more often in diabetics than in non-diabetics.

NIDDM

NIDDM is due to relative insulin deficiency and insulin
resistance. There is a strong genetic predisposition although
other factors such as obesity are important. Concordance in
monozygotic twins is 40–100% and the risk to siblings may
approach 40% by the age of 80. Although the biochemical
mechanisms underlying NIDDM are becoming better
understood, the genetic causes remains obscure. In rare cases,
insulin receptor gene mutations, mitochondrial DNA mutations
or mild mutations in some of the MODY genes are thought to
confer susceptability to NIDDM.

Coronary heart disease

Environmental factors play a very important role in the
aetiology of coronary heart disease, and many risk factors have
been identified, including high dietary fat intake, impaired
glucose tolerance, raised blood pressure, obesity, smoking, lack
of exercise and stress. A positive family history is also
important. The risk to first degree relatives is increased to six
times above that of the general population, indicating a
considerable underlying genetic predisposition. Lipids play a
key role and coronary heart disease is associated with high LDL
cholesterol, high ApoB (the major protein fraction of LDL),
low HDL cholesterol and elevated Lp(a) lipoprotein levels.
High circulating Lp(a) lipoprotein concentration has been
suggested to have a population attributable risk of 28% for
myocardial infarction in men aged under 60. Other risk factors
may include low activity of paraoxonase and increased levels of
homocysteine and plasma fibrinogen.

Lipoprotein abnormalities

Lipoprotein abnormalities that increase the risk of heart
disease may be secondary to dietary factors, but often follow
multifactorial inheritance. About 60% of the variability of
plasma cholesterol is genetic in origin, influenced by allelic
variation in many genes including those for ApoE, ApoB,
ApoA1 and hepatic lipase that individually have a small
effect. Familial hypercholesterolaemia (type II
hyperlipoproteinaemia), on the other hand, is dominantly
inherited and may account for 10–20% of all early coronary
heart disease. One in 500 of the general population is
estimated to be heterozygous for the mutant LDLR gene. The
risk of coronary heart disease increases with age in
heterozygous subjects, who may also have xanthomas. Severe
disease, often presenting in childhood, is seen in homozygous
subjects.

Familial aggregations

Familial aggregations of early coronary heart disease also
occur in people without any detectable abnormality in lipid
metabolism. Risks to other relatives will be high, and known
environmental triggers should be avoided. Future molecular
genetic studies may lead to more precise identification
of subjects at high risk as potential candidate genes are
identified.

Schizophrenia and affective psychoses

A strong familial tendency is found in both schizophrenia and
affective disorders. The importance of genetic rather than
environmental factors has been shown by reports of a high
incidence of schizophrenia in children of affected parents and
concordance in monozygotic twins, even when they are
adopted and reared apart from their natural relatives. The
same is true of manic depression. Empirical values for lifetime
risk of recurrence are available for counselling, and the burden
of the disorders needs to be taken into account. Both polygenic
and single major gene models have been proposed to explain
genetic susceptibility. A search for linked biochemical or
molecular markers in large families with many affected
members has so far failed to identify any major susceptibility
genes.

Congenital malformations

Syndromes of multiple congenital abnormalities often have
mendelian, chromosomal or teratogenic causes, many of which
can be identified by modern cytogenetic and DNA techniques.
Some malformations are non-genetic, such as the amputations
caused by amniotic bands after early rupture of the amnion.
Most isolated congenital malformations, however, follow
multifactorial inheritance and the risk of recurrence depends
on the specific malformation, its severity and the number of
affected people in the family. Decisions to have further
children will be influenced by the fact that the risk of
recurrence is generally low and that surgery for many isolated
congenital malformations is successful. Prenatal
ultrasonography may identify abnormalities requiring
emergency neonatal surgery or severe malformations that have
a poor prognosis, but it usually gives reassurance about the
normality of a subsequent pregnancy.

Mental retardation or learning disability

Intelligence is a polygenic trait. Mild learning disability
(intelligence quotient 50–70) represents the lower end
of the normal distribution of intelligence and has a
prevalence of about 3%. The intelligence quotient of
offspring is likely to lie around the mid-parental mean.
One or both parents of a child with mild learning disability
often have similar disability themselves and may have other
learning-disabled children. Intelligent parents who have one
child with mild learning disability are less likely to have
another similarly affected child.

severe learning disability

By contrast, the parents of a child with moderate or severe
learning disability (intelligence quotient50) are usually
of normal intelligence. A specific cause is more likely when
the retardation is severe and may include chromosomal
abnormalities and genetic disorders. The risk of recurrence
depends on the diagnosis but in severe non-specific retardation
is about 3% for siblings. A higher recurrence risk is observed
after the birth of an affected male because some of these cases
represent X linked disorders. Recurrence risks are also higher
(about 15%) if the parents are consanguineous, because of the
increased likelihood of an autosomal recessive aetiology. The
recurrence risk for any couple increases to 25% after the birth
of two affected children.

Dysmorphology and teratogenesis

Dysmorphology is the study of malformations arising from
abnormal embryogenesis. A significant birth defect affects
2–4% of all liveborn infants and 15–20% of stillbirths.
Recognition of patterns of multiple congenital malformations
may allow inferences to be made about the timing, mechanism,
and aetiology of structural developmental defects. Animal
research is providing information about cellular interactions,
migration and differentiation processes, and gives insight into
the possible mechanisms underlying human malformations.
Molecular studies are now identifying defects such as
submicroscopic chromosomal deletions and mutations in
developmental genes as the underlying cause of some
recognised syndromes. Diagnosing multiple congenital
abnormality syndromes in children can be difficult but it is
important to give correct advice about management, prognosis
and risk of recurrence.

Malformation

A malformation is a primary structural defect occurring during
the development of an organ or tissue. Most malformations have
occurred by 8 weeks of gestation. An isolated malformation, such
as cleft lip and palate, congenital heart disease or pyloric
stenosis, can occur in an otherwise normal child. Most single
malformations are inherited as polygenic traits with a fairly low
risk of recurrence, and corrective surgery is often successful.
Multiple malformation syndromes comprise defects in two or
more systems and many are associated with mental retardation.
The risk of recurrence is determined by the aetiology, which may
be chromosomal, teratogenic, due to a single gene, or unknown.
Minor anomalies are those that cause no significant physical or
functional effect and can be regarded as normal variants if they
affect more than 4% of the population. The presence of two or
more minor anomalies indicates an increased likelihood of a
major anomaly being present.

Disruption

A disruption defect implies that there is destruction of a part of
a fetus that had initially developed normally. Disruptions
usually affect several different tissues within a defined
anatomical region. Amniotic band disruption after early
rupture of the amnion is a well-recognised entity, causing
constriction bands that can lead to amputations of digits and
limbs. Sometimes more extensive disruptions occur, such as
facial clefts and central nervous system defects. Interruption of
the blood supply to a developing part from other causes will
also cause disruption due to infarction with consequent atresia.
The prognosis is determined by the severity of the physical
defect. As the fetus is genetically normal and the defects are
caused by an extrinsic abnormality the risk of recurrence is
small.

Deformation

Deformations are due to abnormal intrauterine moulding and
give rise to deformity of structurally normal parts.
Deformations usually involve the musculoskeletal system and
may occur in fetuses with underlying congenital neuromuscular
problems such as spinal muscular atrophy and congenital
myotonic dystrophy. Paralysis in spina bifida also gives rise to
positional deformities of the legs and feet.

Oligohydramnios

Oligohydramnios causes fetal deformation and is well
recognised in fetal renal agenesis (Potter sequence). The
absence of urine production by the fetus results in severe
oligohydramnios, which in turn causes fetal deformation and
pulmonary hypoplasia. Oligohydramnios caused by chronic
leakage of liquor has a similar effect.
A normal fetus may be constrained by uterine
abnormalities, breech presentation or multiple pregnancy. The
prognosis is generally excellent, and the risk of recurrence is
low except in cases of structural uterine abnormality.