Lecture Notes
复杂疾病的遗传学
张咸宁（细胞生物学与医学遗传学系）
2012/09
I. Overview
Any disease is the result of the combined action of genes and environment.
Classification of genetic disorders:
1. Chromosome disorders:
2. Single-gene disorders:
3. Complex (multifactorial, polygenic) disorders:
4. Somatic cell genetic disorders:
5. Mitochondrial genetic disorders:
Genetic Susceptibility: An inherited predisposition to a disease or disorder which
is not due to a single-gene cause and is usually the result of a complex interaction of
the effects of multiple different genes, i.e. polygenic inheritance.
Liability: A concept used in disorders which are multifactorially determined to
take into account all possible causative factors.
Trait: Any detectable phenotypic property or character.
Qualitative trait: A genetic disease trait that either present or absent. The pattern
of inheritance for a qualitative trait is typically monogenetic, which means that the
trait is only influenced by a single gene.
Quantitative trait: are measurable characteristics such as height, blood pressure,
serum cholesterol, and body mass index. A quantitative trait shows continued
variation under the influence of many different genes.
II. Roles of genetics and environment in disease
In the past most people would have said that all disease has a genetic component
except perhaps for infection and trauma. However, it has become clear that genetic
differences can influence the susceptibility to and progression of infectious agents.
For example, a relatively common 32-basepair deletion in the leukocyte receptor gene
CCR5 confers resistance to HIV infection by the usual sexual routes. For trauma there
may be genetic influences on risk-taking behavior as well as tissue responses to
injury.
Even for “single-gene” disorders there are environmental influences on the
phenotype. A classic example is phenylketonuria (PKU), most often caused by
mutations in the gene for phenylalanine hydroxylase that catalyzes conversion of
phenylalanine and tyrosine. Individuals with PKU, if untreated, develop severe mental
retardation. However, if started in the first month of life on a special diet restricted in
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phenylalanine and supplemented with tyrosine, representing an alteration of the
dietary environment, then these same individuals develop completely normal
intelligence. As another example, we know that different patients with the same
mutations in the cystic fibrosis gene may have vastly different severities of their
disease. This may be due to the influence of unknown “modifier genes” and/or
environmental factors.
There are approaches that can be used to attempt to sort out the contributions of
genetic and environmental factors:

Familial aggregation of disease: This can be measured by the relative risk
ratio, r, which compares the prevalence of the disease in relatives of an affected
proband compared with prevalence in the general population. In practice the ratio is
specific to a particular class of relative, e.g., sibs, parents, etc. The higher the familial
aggregation, the larger the r. If r = 1, then the relative is at no greater risk than
anyone in the general population. Of course, one must always keep in mind that
members of a nuclear family may share both genetic and environmental factors.
 Concordance and allele-sharing among relatives: The closer the genetic
relationship in a family, the more alleles they share in common. For example,
monozygotic twins share 100% of their genes in common, whereas first-degree
relatives, such parents, sibs (including dizygotic twins) and offspring have 50% of
their genes in common. Environmental influences can be evaluated, for example, by
comparing individuals adopted into a family with biological relatives. Similarly,
comparisons of disease frequencies in monozygotic and dizygotic twins reared
together or apart can be useful. This can help to separate the genetic from the
environmental influences and determine the degree of heritability of a trait.
III. Differences and similarities between rare, “single-gene” disorders and
common complex diseases
A. Phenotypes of all genetic diseases are complex traits
Classically there has been a conceptual dichotomy. Simple Mendelian diseases
were considered to be rare, single-gene disorders, whereas complex genetic diseases
were considered to be common, polygenic disorders.
A corollary to this simplistic view was that a specific mutation in a single-gene
disorder would correlate with the presentation and prognosis among different
individuals with that disease. In other words, genotype would predict phenotype.
However, as data began to accumulate, we recognized that the same mutation might
have very different presentations and prognoses for different individuals, even within
the same family. The conclusion is that genetic and environmental modifiers influence
the phenotypic expression even for “simple” Mendelian disorders.
Therefore, single-gene and polygenic diseases represent points on a continuum
and not distinct entities.
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B. Common genetic diseases and complex genetic etiologies
Is a common, complex disease due to the same set of genetic and environmental
influences in each patient with that disorder? The answer is probably not!
Let’s take as a hypothetical example type 2 diabetes mellitus or
non-insulin-dependent diabetes mellitus (NIDDM). Some patients with this disease
may have a primary genetic mutation, whereas others may have a polygenic etiology.
For the latter, let us speculate that there may be 25 genes involved, but for any
individual an average of five genes among these 25 will have the greatest influence;
i.e., not all 25 genes are involved in all individuals. Since there will be a variety of
genetic variations in each of these genes associated with NIDDM, therefore even for
these “common” diseases the composite genotypes for individual patients will be
relatively rare.
IV. Specific Disease Examples
A. Complex diseases may show varying levels of heritability
Heritability (h2) is the percentage of population variation in a trait (or disease) that
is due to genes as opposed to environmental influences. This is often calculated from
twin studies.
CMZ - CDZ
h = ----------------------100 -- CDZ
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CMZ is the concordance rate for monozygotic twins, and CDZ is the concordance
rate for dizygotic twins. For traits that are largely determined by genes, so that MZ
twins show much higher concordance than DZ twins, h2 will approach or exceed 1.
For traits that are largely environmental, so that the concordances for MZ and DZ
twins are almost the same, h2 will approach 0. Some examples are shown in the table
below:
Trait or Disease
Alcoholism
Autism
Cleft lip/palate
Diabetes, type 1
Diabetes, type 2
Measles
Schizophrenia
Concordance Rate
MZ twins DZ twins
0.6
0.92
0.38
0.35-0.5
0.7-0.9
0.95
0.47
0.3
0.0
0.08
0.05-0.1
0.25-0.4
0.87
0.12
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Heritability
0.6
>1
0.6
0.6-0.8
0.9-1.0
0.16
0.7
B. Complex diseases may be caused by various combinations of genes and
environmental factors
Alzheimer disease (AD) is a common neurodegenerative disease with a
prevalence that increases dramatically with age. It is characterized by a progressive
deterioration of memory and higher cognitive functions. Pathological changes include
neuronal degeneration in specific cerebral cortical regions, particularly the
temporoparietal cortex and the hippocampus.
The empiric risk data indicate that by 85 yrs of age, first degree relatives of
patients with AD have 0.38 probability or 38% risk of developing AD.
Complex genetic contributions to AD may come from:
- One or more incompletely penetrant genes that act independently;
- Multiple interacting genes; and/or
- A combination of genetic and environmental factors.
Approximately 10% of AD patients have a monogenic form of the disease with
highly penetrant, age-related, autosomal dominant inheritance. Familial AD presents
earlier in life than typical AD: as early as the third decade (20s) compared with the
seventh to ninth decades for typical AD. The genes involved in autosomal dominant
AD include -amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2
(PS2).
Another gene, APOE, appears to have a strong, though not strictly Mendelian,
influence on the heritability of AD. It encodes apolipoprotein E (ApoE), a protein
component of the low-density lipoprotein (LDL) particle. It is involved in LDL
clearance by interaction with hepatic receptors. ApoE is a constituent of the cerebral
amyloid plaques that are typically seen in AD. ApoE binds A peptide, derived from
the normal amyloid protein precursor and the most important plaque component.
There are three ApoE alleles: 2, 3 and 4.
Sibpair analysis revealed excess allele sharing in the region of the APOE locus.
Association studies between APOE alleles and AD, with appropriately matched
patients and controls, showed that a genotype with at least one 4 allele was observed
2-3 times more frequently in those with AD than in controls in the U.S. and Japan.
Age of onset and APOE genotype in one study of AD patients and controls:
4/4: <10% disease-free by 80 yrs
 2/3: >90% disease-free at 80 yrs

However, the overall predictive value of this genetic factor is poor:

50-75% of 4 heterozygotes never develop AD
 Many with 4/4 live to extreme old age without AD
Because of its poor predictive value and the absence of an effective therapeutic
intervention to prevent onset of the symptoms, testing of asymptomatic individuals for
4 remains controversial.
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There are also environmental factors involved. An association between the
presence of an 4 allele and AD following head trauma is seen in professional boxers.
C. A minority of cases of many common, complex diseases are due to
strong genetic factors showing Mendelian inheritance
Just as most cases of Alzheimer disease are sporadic but a few families show
strong dominant inheritance due to the genes noted above, a number of other common
diseases also show a Mendelian (often dominantly inherited) form in a minority
(typically <10%) of cases. Some examples are shown in the following table:
Common Disease
Mendelian Subtype
Involved Gene
Atherosclerosis
Familial hypercholesterolemia LDL receptor (LDLR)
Breast cancer
Familial breast/ovarian cancer BRCA1, BRCA2
Amyotrophic lateral Familial ALS
Superoxide dismutase (SOD1)
Sclerosis
Parkinson disease
Alzheimer disease
Hypertension
Familial Parkinson disease
-synuclein
Familial AD
PS1, PS2, APP
Liddle syndrome
Renal sodium channel (SCNN1B)
V. How to Determine the Genetic Components of Complex Diseases?
• Family, twin and adoption studies
• Segregation analysis
• Linkage analysis
• Association studies and linkage disequilibrium
• Identification of DNA sequence variants conferring susceptibility
Genome-wide linkage studies (GWAS) followed by positional cloning have been
very successful in identifying causal variants for Mendelian disorders. exome
sequencing has now been applied in multiple situations where (a) several affected
siblings in a family, (b) several unrelated cases and (c) sporadic cases are available for
analysis where the causal variants for a number of Mendelian disorders have been
successfully identified. In addition, exome sequencing has also been shown to be
more robust to study disorders with genetic and phenotypic heterogeneity. It has also
proved viable to study Mendelian disorders if only a single case is available. In
addition, de novo causal variants have also been successfully identified for sporadic
cases. Exome sequencing has also been demonstrated as a powerful tool in diagnostic
application. Integration with linkage and homozygosity data has greatly facilitated the
discovery of causal variants and candidate genes for Mendelian disorders.
GWAS of common diseases have had a tremendous impact on genetic
research over the last five years; the field is now moving from microarray-based
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technology towards next generation sequencing.
VI. Characteristics of Inheritance of Complex Diseases
1. Diseases with complex inheritance are not single-gene disorders and do not
demonstrate a simple Mendelian pattern of inheritance.
2. Diseases with complex inheritance demonstrate familial aggregation, because
relatives of an affected individual are not likely to have disease-predisposing alleles in
common with the affected person than are unrelated individuals.
3. Pairs of relatives who share disease-predisposing genotypes at relevant loci may
still be discordant for phenotype(show lack of penetrance) because of the crucial role
of nongenetic factors in disease causation. The most extreme examples of lack of
penetrance despite identical genotypes are discordant MZ.
4. The disease is more common among the close relatives of the proband and
becomes less common in relatives who are less closely related. Greater concordance
for disease is expected among MZ verse DZ.
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