Polygenic inheritance,

complex diseases
Pharmaceutical Biology II.
Lecture
Ramona Pap – 2023
Complex inheritance
Complex inherited diseases affected by an interaction between collective effects of the genotype at one
or multiple loci either to increase or to lower susceptibility to disease, combined with a variety of
environmental exposures that may trigger, accelerate, exacerbate, or protect against the disease process.

• Inheritance does not follow mendelian patterns

• Complex interactions between genetic and environmental factors

Multifactorial/complex inheritance pattern

Raise/lower
• Collective effect of: genotype (one/multiple loci) susceptibility
environmental exposures Trigger/accelerate/
protect
Qualitative and quantitative traits
• Qualitative trait/Discrete: present One has the
or absent
condition/disease or not.

• Quantitative/Continuous trait: eg.: height, blood pressure,

measurable physiological or BMI, serum cholesterol conc.
biochemical quantities
Genetic analysis of qualitative disease traits

• Familial aggregation: primary characteristic of diseases with complex

inheritance
Concordant: have the same disease
• Two related individuals
Discordant: one is affected, the other is not

Prevalence of the disease in the Case-control studies: patients with

relatives of an affected person
a disease (cases) are compared
• Measure: λr =
Prevalence of the disease in with suitably chosen individuals
the general population without the disease (controls).
Polygenic inheritance is a non-Mendelian form since it is controlled by multiple genes at different loci on different
chromosomes expressed together.
Contribution of genes?
Contribution of environment?
• Compare disease concordance in relatives who are more or less
closely related to the proband.
• Genes are important  concordance increases as the degree of
relatedness increases
Example: monozygotic twins: have alleles in common
parent-child: the child has one allel in common with parent λr
distant relatives

• Separate family environment: compare the incidence of disease in

unrelated family members (adoptees) with biological relatives
Example: MS  λr=20-40 in first degree biological relatives Genetic
λr=1 for children adopted into the family contribution
Twin studies
• Dizygotic (DZ) twins  grow up together in Measure disease
similar environments, but do not share all of concordance in relatives
their genes Separate genetic from
• Monozygotic (MZ) twins  identical genotypes environmental factors
with similar/no similar environments

• Disease concordance in MZ twins:

Sickle cell disease: if one has, 100% the other also
Type I diabetes: if one has, 40% the other also has
Nongenetic factors play a role in the
Disease concordance is less than 100% development of Type I diabetes
• Concordance of MZ versus DZ twins:
MZ and same-sex DZ twins share common: intrauterine environment
sex
usually reared together
Compare the concordance of disease

Show the frequency of disease between relatives who:

Same prenatal environment
Possibly same postnatal environment
Have all their genes in common (MZ twins) 50% of their genes in common (DZ twins)

Strongest for conditions with early onset Greater the concordance in

MZ twins versus DZ twins 
eg.: birth defects genetic contribution
• Twins reared apart:
MZ twins are separated

Observe disease concordance in individuals with identical genotypes grow up in

different environments

eg.: eating disorders  strong environmental influences

• Limitations of twin studies:

1. MZ twins don’t have precisely identical genes or gene expression
2. Environmental conditions may not be the same, especially after leave home
3. Measurements give an average estimate  different conditions in different twin pairs
4. Emotionally close MZ twins like to volunteer in studies  inflates the concordance
rate
Genetic analysis of quantitative traits

• Vary among individuals and important determinants of health and disease

• Normal (gaussian) distribution  mean

• Quantitative phenotype: physiological quantity that

can be measured
• Total phenotypic variance: variance of a measured
quantity in the population

Normal range is important in clinical medicine!  setting the limits

How far is a physiological value from the mean?
Familial aggregation of quantitative traits
Familial aggregation is the more frequent occurrence of a trait in members of a family than among non-related
individuals. It is a common analysis method to determine the genetic contribution to a complex human disease.

Measure the correlation of physiological quantities among relatives

eg.: blood pressure
positive correlation: higher a patient’s blood pressure, the higher
are the blood pressure of patient’s relatives
negative correlation: greater the increase in patient’s values, the
lower the value in patient’s relatives

Estimate genetic influence on a quantitative trait

Characteristics of inheritance of complex diseases
1. Not single-gene disorders and don’t follow simple mendelian
pattern of inheritance

2. Often demonstrate familial aggregation

3. Crucial role of non-genetic factors in disease

4. The disease is more common among the close relatives of the

proband
Digenic Retinitis Pigmentosa

Peripherin
• Patients are heterozygous for No disease
Rom1
• Patients are heterozygous for Both alleles Disease

• No environmental factors

Cell damage
Photoreceptor death
Loss of vision
Cerebral Venous Thrombosis (CVT)

Clots form in the venous system of the brain  occlusion of cerebral veins
• <1 per 100.000 in the population
• Three factors:
a. Missense mutation in clotting factor V (FVL) Genetic
b. Variant of prothrombin factors
c. Use of oral contraceptives Environmental factor

FVL: heterozygous: 7X Oral contraceptive + FVL heterozygosity:

homozygous: 80X modest risk increase
Prothrombin: heterozygous: 3-6X
Oral contraceptive: 14-22X Oral contraceptive + prothrombin heteroz.:
30-150X
 Memo: Homozygous
means two copies of
Alzheimer Disease (AD) the same allele.
Heterozygous means
one of each type of

• Risk factors: age, gender, family history allele, one dominant

and one recessive.

early onset AD: three rare autosomal dominant forms

late onset AD: no mendelian inheritance pattern

but familial aggregation! ε2
• Significant genetic factors: apolipoprotein E (APOE) ε3
ε4
ε4 homozygotes Many ε4 homozygotes
ε4/ε3 heterozygotes Earlier And 50-75% of
other genetic and
onset persons with one ε4
Other genotypes environmental factors
allele never develop
disease.
Multifactorial congenital malfunctions
Neural Tube Defects (NTD)
• Anencephaly: forebrain, overlying meninges, vault of the Multiple genetic and
skull and skin are all absent environmental
• Spina bifida: failure of fusion of the arches of the vertebrae factors

Not all mothers of NTD infants

Maternal folic acid deficiency
Threshold: 200 µg/L in serum
Elevated homocysteine levels
Dietary intake
Genetic variant of MTHFR gene  instable enzyme
5%-15% are homozygous  increased risk
with low folic acid are homozygous
for the mutant allele of MTHFR
Other unknown genetic factors
Dietary deficiency alone  in
pregnancy: 400-800 µg/day
Mental illnesses
1. Schizophrenia
• 1% of the population
• MZ concordance: 40-60%
DZ concordance: 10-16%
• Genetic contribution: 22q11 deletion  DiGeorge syndrome
25% of patients develop schizophrenia

2. Bipolar disease
• 0,8% of the population
• MZ concordance: 62%
DZ concordance: 8%
• Disease risk is elevated in relatives of affected individuals
Coronary artery disease (CAD)

• Few mendelian disorders

eg.: hypercholesterolemia: autosomal dominant
• Most cases show multifactorial inheritance
• Myocardial infarction (MI)
Risk factors: female proband Suggest greater genetic
contribution  increased
young proband (>55 years) risk for proband’s relatives
diabetes, hypertension
smoking
obesity
Genetic counselling
• Measuring actual recurrence risks in collection of families  average
recurrence risks
• Important:
1. The risk is much higher in first-degree relatives
2. Risk is calculated from the observations in similar families
(for relatives with the same degree of relationship)
3. The risk increase with more than one affected relative
severe form and early onset
mating between relatives
4. The children with one common parent are second-degree relatives, not first-
degree
5. Single-gene disorders with Mendelian inheritance is masked by small family
sizes and incomplete penetrance