Polygenic Disorders

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Polygenic Disorders
Dr John Loughlin
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Single gene trait
Environment
GENE
PHENOTYPE
Other Genes
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Polygenic trait
Environment
Gene1 Gene 2 Gene 3 Gene 4
PHENOTYPE
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Single gene diseases versus polygenic diseases
Whereas the mutations causing single gene
diseases have a major impact on the function of
the gene product, and are therefore rare, those
causing polygenic disease have a more moderate
effect, and are therefore relatively common
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Polygenic trait characteristics

• Common
• Unlike single gene traits
• Multi-gene involvement
• Each gene has varying effects on trait occurrence
  and development
• Often have major non-genetic influences
• i.e. environmental factors
• Unclear transmittance patterns

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Frequency of several polygenic diseases
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Frequency of several polygenic diseases
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An osteoarthritic hip
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OA prevalence in the UK

• 2 million adults
• Majority aged gt 60 years
• Over 1 million GP appointments each year

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An osteoarthritis pedigree
An affected individual with unaffected parents
Late-onset disease with few members of the
younger generation yet affected
Affected individual joining the family,
emphasizing the common nature of the disease
Overall - no clear inheritance pattern
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How does one initially assess whether such a
disease has a genetic component?

• Twin pair studies
• Relative risk studies

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Twin-pair studies 1 in 89 deliveries
1/3 Monozygotic
2/3 Dizygotic
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Concordance rates
DZ
MZ
Cystic Fibrosis
100
25
Die on a Tuesday
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14
Hypertension
30
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Rheumatoid Arthritis
30
5
Type I diabetes (IDDM)
36
5
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Potential pitfalls of twin pair studies

• MZ twins are the same sex whereas 50 DZ twins
  arent
• Remedy - use same-sex DZ twins
• MZ twins often treated differently than DZ twins,
  which could influence behavioral traits
• Remedy - study twins separated at birth (if
  enough!)
• Intrauterine differences
• MZ twins share more intrauterine tissues than DZ
  twins during gestation, making it difficult to
  distinguish intrauterine environmental causes
  from genetic causes
• Bias of ascertainment
• People often focus on twins who have strikingly
  similar behavioral traits but overlook those who
  dont

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Allele sharing in relatives
2nd
2nd
1st
1st
2nd
0
1st
3rd
proband
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Allele sharing in sibs
What is the frequency of disease in the siblings
of affected individuals compared to the
population frequency?
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Sibling recurrence risk ratio - ?s
Risk to a sib
?s
Population prevalence
Autism 145 Type I diabetes 15 Osteoarthritis
4.5 No genetic component 1.0
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Heritability

• The proportion of the causation of a character
  that is due to genetic causes

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Estimated heritability of osteoarthritis at
different sites
Cervical Spine
Lumbar Spine
Hip
Knee
Hand
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60
40
80
100
0
Spector MacGregor, Osteoarthritis and
Cartilage, 2003
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Overall, twin pair and relative risk studies
enable one to assess whether a common disease has
a genetic component
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Two types of polygenic traits

• Continuous
• Also termed quantitative
• Discontinuous
• Also termed dichotomous or qualitative

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Continuous trait
F R E Q U E N C Y
Phenotype parameter i.e. Height , Blood pressure
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How do genes generate such a normal
distribution?
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One locus with two alleles of equal frequency
A - big effect a - small effect
1
Aa
Number of copies of a big effect allele
genotype frequency
2
0
aa
AA
70
80
90
100
110
120
130
Trait measure
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Two loci with two alleles each
2
AAbb AaBb aaBB
Number of copies of a big effect allele
3
1
Aabb aaBb
AABb AaBB
genotype frequency
0
4
aabb
AABB
70
80
90
100
110
120
130
Trait measure
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Three loci with two alleles each
3
AABbcc AAbbCc AaBbCc AabbCC AaBBcc aaBBCc aaBbCC
4
2
AABBcc AABbCc AAbbCC AaBbCC AaBBCc aaBBCC
Number of copies of a big effect allele
AAbbcc AaBbcc AabbCc aaBbCc aabbCC aaBBcc
genotype frequency
1
5
Aabbcc aaBbcc aabbCc
AABBCc AABbCC AaBBCC
0
6
aabbcc
AABBCC
70
80
90
100
110
120
130
Trait measure
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Three loci with two alleles each
genotype frequency
70
80
90
100
110
120
130
Trait measure
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Conclusiongenes can generate a continuous trait
when they act together
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Discontinuous Traits

• Yes/No characteristic
• The disease manifests once a certain threshold of
  susceptibility has been surpassed

Threshold Model of Susceptibility
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Distribution of liability
Threshold
unaffected
affected
high liability
low liability
average liability
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Crossing the threshold

• A combination of the genes one has inherited and
  the exposure one has had to environmental risk
  factors

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The sibs of an affected person have a higher
liability
Threshold
Distribution of liability in the general
population
unaffected
affected
Distribution of liability in the sibs of affected
people
Low liability
High liability
Average liability in general population
Average liability among sibs of affected people
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Recurrence risk

• Risk that a disease will occur elsewhere in a
  pedigree, given that at least one member of the
  pedigree exhibits the disease
• RR increases as the number of affected family
  members increase

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Why are polygenic diseases so common?
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Several possibilities

• High new mutation rate
• Not likely
• Onset of symptoms after reproductive age
• Arthritis
• But are older people really selectively
  unimportant?
• The mutations offer a selective advantage
• Has been suggested, for example type II diabetes

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Type II diabetes

• Hyperglycaemia, developing in the adult
• Pancreas produces insulin but cells are resistant
• Polygenic disease with major environmental risk
  factors
• High calorie intake and low exercise
• Up to 10 times more prevalent in the obese
• Prevalence is increasing as populations become
  westernized

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Type II diabetes and the thrifty gene hypothesis

• Metabolically thrifty genes
• Permit efficient food utilization, fat deposition
  and weight gain at occasional times of food
  abundance
• Make the bearer able to survive periods of famine
• Examples of thrifty genes include those resulting
  in high levels of insulin and leptin
• Insulin - mediates the uptake of glucose by cells
• Leptin - hormone released by fat cells that
  regulates appetite

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Pre-modern times
Genes persist as they offer a survival advantage
Modern times
Premature death
Genes lost? Frequency of disease will peak and
then reduce?
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Jared Diamond (2003) The double puzzle of
diabetes. Nature 423599-602
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The end Fridays lecture Mutation and Disease