Coverage of chapter 8-11: Genetics of common disorders with complex inheritance, Genetic variation, Human gene mapping and disease gene identification, Principles of molecular disease
Chapter 8: Genetics of Common Disorders with
Complex Inheritance
Multifactorial/complex inheritance pattern = familial aggregation (clustering) of a disorder in
absence of mendelian inheritance pattern resulting from complex interactions between genetic
and environmental factors
BUT: familial aggregation does not mean that a disease must have a genetic contribution!
Relatives of an affected individual are more likely to experience same gene-gene and
gene-environment interactions
o 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 monozygotic twins.
Counseling risk relying on empirically derived figures
=recurrence risk observed in similar families for relative with same degree of
relationship
Qualitative versus quantitative
Genetic analysis of qualitative disease traits
Qualitative (discrete) = a genetic disease that is either present or absent
[quantitative = measurable physiological or biochemical quantities such as height, BP, serum
cholesterol, BMI]
Concordance = when two related individuals in a family have the same disease
dissect the contribution of genetic from environmental influences
o Caution: lack of penetrance or phenocopy may explain concordance of
phenotypes in absence of same genotypes or vice versa
Disconcordance = when only one member of the pair of relatives is affected and the
other is not
The familial aggregation of a disease can be measured by comparing the frequency of the disease
in the relatives of an affected proband with its frequency (prevalence) in the general population.
Relative risk ratio λr is defined as:
subscript r for λ is used to refer to relatives; e.g., r =s for sibs, r =p for parents
If λr = 1 relative is no more likely to develop disease than any other individual
the larger λr is, the greater is the familial aggregation
the more common a disease is, the greater is the likelihood that aggregation may be just
a coincidence rather than a result of sharing the alleles that predispose to disease
one would expect λr to be greatest for monozygotic twins, then to decrease for first-
degree relatives such as sibs or parent-child pairs, and to continue to decrease as allele
sharing decreases among the more distant relatives in a family
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,Case-control studies
other way to assess possible genetic contribution to familial aggregation of a disease
frequency with which the disease is found in the extended families of the cases (positive
family history) is compared with the frequency of positive family history among suitable
controls, matched for age and ethnicity, but who do not have the disease. [e.g. spouses or
adopted family members ]. Other frequently used controls are patients with unrelated
diseases matched for age, occupation, and ethnicity.
o many different kinds of errors or bias
o e.g. ascertainment bias: difference in likelihood that affected relatives of the
cases will be reported to the epidemiologist as compared with the affected
relatives of controls)
o e.g. recall bias or confounding factor in choice of controls
Twin studies
both monozygotic (MZ) and dizygotic (DZ)
MZ have identical genotypes at every locus, incidence 0.3% of all births
Examination of concordance is powerful method to assess influence of genotype alone
e.g. concordance of 100% or degree of concordance MZ twins > DZ twins pleads
(mono)genetic factor as a cause
DZ twins share ~50% of alleles like all siblings; incidence 0.2-1%
Limitations:
o Genetic: somatic rearrangement and X-inactivation difference in MZ females
o Difference between different twin pairs (e.g. nongenetic phenocopy
o Environment differences: intratuterine (!) and especially after adolescence
o Ascertainment bias (volunteer or population-based)
Genetic analysis of quantitative disease traits
= measurable physiological or biochemical quantities such as height, BP, serum cholesterol, BMI
Normal distribution versus normal range
Familial aggregation studies
normal (Gaussian) distribution, mean (µ) and variance/standard deviation
family studies measure correlation: tendency for actual values to be more similar among
relatives than among the general population
o r is coefficient of correlation
o correlation can be positive (r=1) or negative (r=-1) or completely absent (r=0)
assumption that the degree of similarity in the values of the trait measured among
relatives is proportional to the number of alleles they share at the relevant loci
the more closely related individuals are, the more likely they are to share alleles at loci
that determine a quantitative trait and the more strongly correlated will be their values
o But, correlation reflects the influence of both heredity and common
environmental factors. A correlation does not indicate that genes are wholly
responsible for whatever correlation there is.
Heritability (h2)
= fraction of the total phenotypic variance of a quantitative trait that is caused by genes
= measure of the extent to which different alleles at various loci are responsible for the
variability in a given quantitative trait seen across a population.
the higher the heritability, the greater is the contribution of genetic differences among
people in causing variability of the trait.
H2 = between 0 (no gene contribution) to 1 (genes totally responsible)
o E.g. for length H2=0.8, indicating important role for genotype
36
, Somewhat theoretical estimate with limitations:
o Correlation in family studies may not reflect only genetic factors, but
environmental as well
o Even high heritability does not reveal underlying mechanism of inheritance
o Cannot be considered in isolation from the population group and living
conditions in which the estimate is being made (cave extrapolation)
The formula for calculating h2 is given by (DZ=dizygotic twins, MZ=monozygotic twins)
Limitations
Cave: heritability from twin studies cannot always be extrapolated to a population
as a whole, to different ethnic groups or to the same group if socioeconomic
conditions change over time
Studies do not specify which loci and alleles are involved/how many/ mechanism of
interaction with environment
Genetic and environmental modifiers of single-gene disorders
Difference in phenotype sometimes perfectly explained by allelic heterogeneity
o E.g. certain mutation in CF predicting need for ERT for pancreatic insufficiency
Sometimes variability still unexplained after correction for allelic heterogeneity
attempt can be made to determine relative contribution o phenotype
o E.g. heritability of FEV1 percentage is 0.5 (MZ vs DZ twins study) suggests role
of modifier genes as well as environmental factors
Examples of multifactorial traits for which genetic and environmental factors are known
Digenic retinitis pigmentosa
Patients are heterozygous for two mutations in two different genes
One heterozygous mutation or one homozygous mutation does not lead to disease
= simplest example of multigenic trait
Venous thrombosis
Three relatively common factors that each increase the risk of abnormal coagulability of
the clotting system:
o a common missense mutation in a clotting factor, factor V;
o another common variant in the 3' untranslated region of the gene for the clotting
factor prothrombin;
o use of oral contraceptives
Factor V Leiden is mutant allele Arg506Gly: allele freq 2.5% in white people and rarer in
other populations
risk of e.g. cerebral vein thrombosis is 7 times higher than in general population for
heterozygous carriers and 80x higher for homozygotes
However, these factors cannot cause significant disease even if all together in one
person, since incidence of thrombotic events is relatively small: controversy on whether
and when to screen for mutations (e.g. start of oral contraceptives in all white women?)
important to distinguish relative risk (increase) from absolute risk
Hirschsprung disease (HSCR)
= aganglionic colon incapable of peristalsis, resulting in severe constipation, symptoms
of intestinal obstruction and massive colon dilatation (megacolon) proximal to the
aganglionic segment
Incidence 1 in 5000 newborns
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