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PSYC 3102: Introduction to Behavioral Genetics
Lecture 10
Disorders with Complex Genetics (DCGs)
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Disorder for which we know there are genetic effects, but don’t have a clue of what exactly
they are
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They usually are not due entirely to genetics
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Ex: diabetes; high blood pressure, Alzheimer’s disease; nearly all psychopathology; virtually
all other behavioral problems
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More frequent than Mendelian disorders
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Often have frequencies around 1%-3%
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(compared to Mendelian disorders – 1/5000 to 1/10000)
Alzheimer’s Disease (AD)
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Tends to have a late onset (mid to late adulthood)
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First symptoms generally deal with memory, there is usually forgetfulness of recent events
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This memory loss is usually attributed initially to age, initial stages are usually very difficult
to diagnose
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As the disease progresses, forgetfulness becomes more severe and more frequent
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In later stages, they forget who the people around them are, can get lost if out walking
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As disease progresses there can also be loss of verbal ability, incontinence, marked changes
in personality, loss of motor ability
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AD does not kill people, but they usually become bedridden and open to other problems
(pneumonia, opportunistic infections) or have bad falls that lead to death
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Diagnosis—can be determined by skilled physician, however the gold standard is still at
autopsy, where neurofibrillary tangles and plaques (accumulations of amyloid proteins) are
found in the brain
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Biggest risk for developing AD is AGE
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Average lifespan has been increasing, so we are seeing more occurrences
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Cost of care ($50,000-$60,000/yr) is high, so there have been a lot of efforts to learn more
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Onset can occur in 40s (rare) or not until 90s
Classification
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Age of onset – early or late
early is usually before age 65
late is usually 65 or older
early onset cases are relatively rare (<10% of AD cases)
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Family history – positive or negative
criterion varies but usually positive family history involves a close family member
(parent, sib)
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Correlations found between these criteria of early/late and FHP and FHN:
Early Onset
Late Onset
Family
History
Positive
*Strongest
Correlation
Family
History
Negative
2 Important Findings

(1) 20-30 yrs ago pedigrees were studied and it was found that the disorder ran as a
dominant gene effect in a FEW pedigrees
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(2) Nearly all cases of Down’s Syndrome developed AD-like brain pathology (plaques and
tangles)
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So further study was done on dense pedigrees and on chromosome 21
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In a few of the dense pedigrees a mutation was found in the APP gene (Amyloid Precursor
Protein)
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This mutations acted as a dominant gene with an almost 100% penetrance
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2 more rare mutations found at different loci (different chromosomes as well) that also act as
dominant genes
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Consequently this means that there are a FEW RARE Mendelizing forms that cause this
disorder/syndrome
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All together they account for ~2-3% of all cases

The same is true of the breast cancer genes (BRC1 and BRC2)
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Another gene was found (but they weren’t specifically looking for this) that acts as a
susceptibility gene which increases risk of AD (but DOES NOT determine fate)
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This was at the APO-E locus—there are 3 alleles: E-2; E-3; E-4
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E-2: has protective factor, more alleles one has of this, the lower the risk
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E-3: normal/neutral
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E-4: has risk factor, more alleles one has of this, the higher the risk
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Highest risk=E-4/E-4; Lowest risk=E-2/E-2
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Mechanism of how this works is not known
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Controversy over testing… is discouraged in part because nothing can be done and there is
very limited predictive value
Theories
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Mendelizing + phenocopy theory
o Mendelizing: cases of AD are due to single genes (extremely rare variants that
probably aren’t fully penetrant)
o Phenocopy: an environmentally produced syndrome that resembles a genetic
disorder – better definition  environmental insult that will cause the disorder in
anyone, regardless of genotype
o Ex. mental retardation – there are 100’s of single genes that can cause it (we
looked at PKU and Fragile X), but high lead exposure or brain injuries can also
cause it (=phenocopies)
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Multifactorial Model
o Many different factors (genes and environment) come into play and influence risk
o Main difference between the two theories is that in the Multifactorial Model, the
risk factors add up
o Polygenic Inheritance – many genes contribute to risk and probability, like being
dealt a hand of cards
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Polygenic/Multifactorial Threshold Model (Figure in text)
o Genetic and environmental contribute to one’s liability/susceptibility
o Attempts to explain discontinous genotypes
o Risk adds up until it crosses a certain threshold, then the disorder occurs
o everybody has liability, but differ in amount
o Used to explain such things as polydactly (many digits) in mice—there is genetic
influence, you can breed lines with or without it, but there are also environmental
factors (stress during pregnancy)
Mendelizing
+ Phenocopies
Multifactoral
Model
Most beliefs are here in the middle
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The Polygenic Threshold Model is the most common model (and most favored) for
PSYCHOPATHOLOGY
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Models can get much fancier!!
The DCG issue isn’t about finding genes, but about trying to find something about the biology
about the disorder in order to develop treatments and interventions. Genetics is only a tool, not
the end to be achieved.
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Example: Discovery of the APP locus
o APP mutant mice were developed to use as an animal model
o Led to research in the development of plaques