INHERITANCE OF COMPLEX DISORDERS

Dr. Karen Weissbecker

LEARNING OBJECTIVES_______________________________________________

1. Explain the principles of multifactorial inheritance in normal human traits and the
multifactorial nature of complex disorders
2. Define non-Mendelian mechanisms such as: reduced penetrance, variable expressivity,
anticipation, delayed age of onset, uniparental disomy, mosaicism, genomic imprinting
and unstable repeat expansion.
3. Explain how these mechanisms of non-Mendelian inheritance affect phenotypic
expression and recurrence risk of genetic disorders.
4. Describe how environmental factors may interact with genetics to affect phenotype
expression or mitigate disease in a genetically-predisposed individual
5. Define heritability and explain its usefulness in understanding the genetic role in a given
trait or disorder
6. Explain general approaches to determining the significance of genetics in traits and
disorders.

KEY POINTS________________________________________________________
“Complex Disease or Trait”
• disease or trait resulting from complex interactions between genes and the
environment
• runs in families but does not fit single gene Mendelian
• often exhibits things listed below
• often common disorders
• often have to use empirical risk values for counseling

Factors in complex disorders:

1. Reduced Penetrance - frequency of expression of a genotype, or proportion of

individuals who have the disease allele(s) who do not express clinical symptoms.
2. Variable expressivity- – different clinical expression or severity due to same gene. The
extent to which the genetic disorder is evident in an individual carrying the gene.
Problem can be that an affected person with mild phenotype are misdiagnosed
3. Heterogeneity - Different genetic loci produce phenotypes that are clinically
indistinguishable – e.g.: Albinism, deafness, elliptocytosis (Rh linked, not linked),
Alzheimer’s. (Heterogeneity includes possibility of mix in of sporadic cases)
Interlocus heterogeneity - more than one loci causes the disease
Intralocus heterogeneity - more than one allele can cause the disease.
e.g. phenylketonuria exhibits different degrees of severity.
4. Phenocopies: environmental causes that look familial
mimic a phenotype that is usually determined by a specific genotype, but is produced
instead by an environmental cause or the interaction of an envi. factor with a different
genotype. (e.g. retinoic acidopathy and DeGeorge syndrome)

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Factors in complex disorders (continued)

5. Age-dependent penetrance – younger siblings may not yet express phenotype

6. Modifying genes or gene-gene interactions – many genes of small effect can modify the
phenotype of a single major gene
7. Genotype- environment interaction: differences between genotypes with respect to risk
factors variability (e.g. one genotype does not respond to dietary treatments) or
genotype/risk association dependent on presence or absence of envi. factors. i.e.
fauvism
8. Pleiotrophy – if a single locus produces effect on several traits.
9. Polygeneic or multifactorial inheritance – (see below)

Multifactorial Inheritance

A. Polygeneic trait - is one determined by many genes of small and equal and additive effects.
So a large number of genetic loci are postulated to contribute equal and additive effects in
the expression of that trait. Assume it is completely genetic

B. Multifactorial inheritance - a mixture of many genes of small effect acting together with
environmental risk factors.

Threshold model - distribution of liability for a trait or disease determined by both genes
and envi. at a certain threshold, the person is affected. (overhead). Typically, one sex is
more often affected than the other - assume there is a different threshold

Multifactorial inheritance - Criteria

a. Correlation between relatives is proportional to the genes in common. (So there is a
fall off in freq of affected as you go from first to 2ond to 3rd degree relatives)
b. Recurrence risk is higher when more than one family member is affected or the
disorder is more severe in expression.
c. Disorder is present when a threshold is reached on a continuous or discontinuous
scale
d. Occurrence may differ based on sex, and recurrence risk is higher for relatives of
the patient of the less susceptible sex. (will come back to this later)
e. Consanguinity poses greater likelihood of occurrence or recurrence.
f. For a quantitative trait: the mean value for offspring is 1/2 way between the mean
value of the parents and that of the general population.
3. Use empirical risks for counseling.

C. Genetic and Environmental Interaction

D. Quantitative traits
1. Difference is in defining phenotype vs. trait (cholesterol verses hypercholesterolemia)
2. Even quantitative traits can have major influence from a single gene w/ underlying AD or
AR inheritance

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How do we know it is genetic?

Familial Aggregation
1. Relative risk of disease = compare the risk to a specific relative type (eg. siblings) to
the risk in the general population
2. Correlation coefficient (for quantitative traits); Concordance rates for qualitative
traits. These can be used to estimate the relative contribution of underlying genetic
components
Heritability - the proportion of the total phenotypic variation of a trait that is due to genetics.
OR relative contribution of genetic effects to the total variation of the trait
in the population
This is a population statistic so we cannot infer, for example, from a h2 of 0.5 that 50% of
an individual’s personality or IQ, or phenotype, is genetically acquired.

Finding genes –
Association and Linkage analyses

Nontraditional modes of inheritance (details in other lectures)

A. Mitochondrial Inheritance - also known as maternal inheritance, applies to genes in

mitochondrial DNA.

B. Mosaicism - Two cell lines of different genotype or karyotype, derived from a single zygote.
This can results from a new mutation in a precursor cell, or during tissue differentiation-
so you can either have mosaicism within a cell type or between cell type. E.g. skin verses
blood.
Somatic mosaicism
Gametic mosaicism
Chromosomal mosaicism

C. Uniparental disomy - Both chromosomes of a pair come from one parent and none from the
other parent.
1. Isodisomy - Both chromosomes from one parent are identical.
2. Heterodisomy - Both chromosomes from one parent are different.

D. Genomic imprinting:
1. Definition: Modification of genetic material that takes place depending on
whether the genetic information is derived from the mother or the father.
2. Examples:
•Angelman syndrome and Prader Willi
•Beatutiful buttocks example in sheep
•Huntington’s: an earlier age of onset is observed depending on whether the HD
gene was transmitted from Dad rather than Mom. The explanation for this
observation leads us to our next, new genetic phenomena:

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E. Heritable unstable elements:
1. Trinucleotide repeat regions (eg CAG, CAA etc) become unstable and during
reproduction tend to increase the number of trinucleotide repeats, resulting in gene
abnormality and disease expression. (Fra X , Huntingtons, mytotonic dystrophy)

2. Anticipation: increase in severity or decrease in age of onset of a disorder in

successive generations. So in the case of HD, the trinucleotide repeats become
greatly increased if transmitted through a male (rather than a female) and result in
the earlier age of onset I mentioned. (slide - Manic depression)

F. Copy Number Variants: Segments of DNA that are 1 kilobase or larger and present at a
variable copy number in comparison with a reference genome
• Copy number variants are mutations and can include deletions, insertions, and
duplications
• Implicated in schizophrenia, autism, developmental delay

G. Epigenetics

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