Transcript HGSS2 DCGs (Graduate)

Disorders with Complex Genetics
Alzheimer’s Disease
Signs & Symptoms:
• Memory loss for recent events
• Progresses into dementia  almost total memory loss
• Inability to converse, loss of language ability
• Affective/personality disturbance (fatuous, hostile)
• Death from opportunistic infections, etc.
Confirmation of Diagnosis:
• Neuronal (amyloid, b amyloid, Ab amyloid) plaques
• Neurofibrillary tangles
• Brain Atrophy
Neuronal Plaques in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html
Neurofibrillary Tangles in Alzheimer’s Disease
From http://www.rnw.nl/health/html/brain.html
Plaques and neurofibrillary tangles
From Department of Pathology, Virginia Commonwealth University
http://www.hosppract.com/genetics/9707gen.htm
Brain Atrophy in AD
WRONG!
http://abdellab.sunderland.ac.uk/lectures/Neurodegeneration/References/Brain_Neurons_AD_Normal.html
Classification:
(1) FAD v SAD: Familial AD versus Sporadic AD
• No complete consensus
• Usually FAD = at least 1 first degree relative affected
• Sometimes 2 second degree relatives
(2) Early v Late Onset:
• Early onset (EOAD) = usually before 65
• Early onset correlated with FAD
• LOAD = late onset AD
Alzheimer’s Disease, Type 1:
•Several mutations in APP gene on chromosome 21
•Most common = Val717Iso
•Produce abnormal beta amyloid fragment
•15%-20% of early onset, familial AD
•Autosomal dominant
http://ghr.nlm.nih.gov/condition=alzheimerdisease
http://perso.wanadoo.fr/alzheimer.lille/APP/APPmutations.html
Alzheimer’s Disease, Type 3:
•Mutations (> 130) in the presenilin1 gene on chromosome
14
•Most mutations lead to amino acid substitution
•Overproduction of the beta amyloid fragment
•30% - 70% of early onset, familial AD
•Autosomal dominant
Alzheimer’s Disease, Type 4:
• Mutations in the presenilin2 gene on chromosome 1
• 2 alleles: Asn141Iso and Met239Val
• Overproduction of the beta amyloid fragment
• < 5% of early onset, familial AD (only a few
families world wide)
• Autosomal dominant
Alzheimer’s Disease, Type 2:
• Epsilon 4 (e4, AKA E4) allele of the Apolipoprotein E
(ApoE) gene on chromosome 19 confers risk
• Epsilon 2 (e2, AKA E2) allele of the Apolipoprotein E gene
on chromosome 19 confers protection
• Mechanism unclear; ApoE is a very low density lipoprotein
that transports cholesterol
• Most cases are late onset, familial
• Susceptibility Locus
Prevalence of APOE genotypes in
Alzheimer’s disease (AD) and controls.
Genotype:
Controls
AD
E2/E2
1.3%
0%
E2/E3
12.5%
3.4%
E2/E4
4.9%
4.3%
E3/E3
59.9%
38.2%
E3/E4
20.7%
41.2%
E4/E4
0.7%
12.9%
Jarvik G, Larson EB, Goddard K, Schellenberg GD, Wijsman EM (1996) Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a
community-based sample. Am J Hum Genet 58:191-200
http://www.hosppract.com/genetics/9707gen.htm
Two Major Hypotheses for AD:
b amyloid protein (BAP) v. tau
1. BAPtists: The accumulation of a fragment of the amyloid
precursor protein or APP (the amyloid beta 42 residue fragment or
Ab-42) leads to the formation of plaques that somehow kill
neurons.
2. TAUists: Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.
(Recently a presenilin hypothesis has been proposed by Shen
& Kelleher (2007), PNAS, 104:403-408.)
Amyloid Hypothesis
(it’s the plaques, dummy)
1. The amyloid precursor protein (APP) is broken down by a series of
secretases (see next two slides).
2. During this process, a nonsoluble fragment of the APP protein (called Ab42) accumulates and is deposited outside the cell.
3. The nonsoluble or “sticky” nature of Ab-42 helps other protein fragments
(including apoE) to gather into plaques.
4. Somehow the plaques (or possible the migration of Ab-42 outside the
cell) cause neuronal death.
5. PSEN1 & PSEN2 genes  subunits of g secretase.
Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to
be important for neuronal growth, survival, and repair.
From: www.niapublications.org/pubs/unraveling/01.htm
Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or
Ab.
From: www.niapublications.org/pubs/unraveling/01.htm
Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the
plaques seen in the AD brain.
From: www.niapublications.org/pubs/unraveling/01.htm
b-secretase Pathway:
(not drawn to scale)
APP Protein:
b
a
g g
(1) b-secretase cuts APP protein, giving:
(2) g-secretase cuts this residue, giving:
Ab40 Fragment
Soluble
Ab42 Fragment
Unsoluble,
aggregates into
plaques
or
Tau Hypothesis
(it’s the tangles, dummy)
1. Ordinarily, the t (tau) protein is a microtubule-associated protein that
acts as a three-dimensional “railroad tie” for the microtubule. The
microtubule is responsible for axonal transport.
2. Accumulation of phosphate on the tau proteins cause “paired helical
filaments” or PHFs (like two ropes twisted around each other) that
accumulate and lead to the neurofibrillary tangles (NFT). PHFs are the
main component in NFTs.
3. Impaired axonal transport is the probable cause of cell death.
4. Focus on MAPT gene (microtubule-associated protein tau)
5. Not in favor anymore.
Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as
“ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing
the structure of the microtubule. Loss of axonal transport results in cell death.
AD: The Great Unknown:
What is causing the majority of AD cases?
1. Unknown Mendelian forms (probably not)
2. Unknown major loci (probably not)
3. Phenocopies
4. Multifactorial threshold
a. Unidimensional
b. Heterogeneity
Phenocopy
Environmental insult that will produce the disorder
in anyone regardless of genotype
• Heavy metal poisoning and ID
• Amphetamine (stimulant) psychosis
Head injury: possible phenocopy for ADS
Testing a helmet. From: http://dailysanctuary.com/a-rare-photos-from-the-past/
Multifactorial Threshold Model
• Many alleles with “low” penetrance.
• Most people will have several risk alleles.
• Many environmental factors.
• Genetic and environmental factors
add together  liability
•Once liability reaches a certain value (i.e., the
threshold) a disease process begins.
Multifactorial Threshold Model
Notes:
• Alleles can be common or rare
• Factors can be multiplicative (taking
the log makes them additive)
• Central limit guarantees a normal
distribution to liability
• Can have more than one threshold
Frequency
High
Unaffected
Affected
Low
Low
Medium
Liability
High
Heterogeneity I:
Mendelian/Phenocopy
• Many rare alleles with high penetrance (“Mendelian”
forms of the disorder).
• Few will have two or more of these AD alleles.
• Non familial cases due to phenocopies.
Heterogeneity II:
Multifactorial
Several pathways to AD,
each sufficient to cause the disorders
Current theories:
• Protein accumulation:  placques & tangles
• Inflammation: Unregulated activation of glia
• Lipid distribution: Lipid membrane site of APP cleavage.
Unidimensional vs Heterogeneity
Multifactorial Threshold Model
UMTF v HMTF
• UMTF: different mechanisms can compensate
• HMTF: other mechanisms cannot compensate
E.g., In the HMTF model, if a person passes the threshold on the
cholesterol dimension they will develop AD regardless of their liability on
other dimensions. In the UMTF model, low liability on endocytosis can
compensate for high liability on cholesterol
Note Well:
Mathematics allows for BOTH
unidimensional and heterogeneity MFT
models at the same time.
From Karch & Goate (2014), Biological Psychiatry preprint
From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87
Alzheimers Disease
http://www.ambion.com/tools/pathway/pathway.php?pathway=Alzheimer's%20Disease%20Pathway
Current gene candidates for AD:
• Changes too rapidly to keep track of.
• Go to http://Alzgene.org for latest list
DCGs: Three Models
Gibson (2012) Nature Genetics
1.Infinitesimal model (CDCV)
2.Rare allele model (CDRV)
3.Broad sense heritability model
Cases with no known etiology:
(theoretical extremes)
Mendelian/
Phenocopy
Disease (Genetic)
Heterogeneity
Multifactorial/
Threshold
CDCV
Common disease/
common variant
CDCV
Common disease, common variant
1.Many risk alleles
2.Common (MAF > 1%)
3.Add together  risk
Rare Variants
Common Disease, Rare Variant (CDRV_
1.Many variants with
frequencies < 1%
2.Large effect size
3.Prob(Dis | variant) is large
4. genetic heterogenetity
Broad sense
heritability
1.Significant dominance and
epistatic variance
2.Gene-environment interaction
3. Epigenetic effects
small
Effect Size
large
Current Gospel
Rare
Common
Allele Frequency
Rare Variants:
Advantages:
1. Mendelian disorders are rare
2. Selection vs alleles reducing fitness
Disadvantages:
1. Inconsistent with recurrence risks
2. GWAS has found common variants
Common Variants:
Advantages:
1. GWAS has found common alleles
Disadvantages:
1. Still have “missing” h2
2. Statistical effects vs functional effects
Implications
CDCV = More GWAS!
CDRV = Wait till sequencing is mature!
Broad h2 = ?
Animal Models
Human APP
gene
Mice gratia http://www.kidscolorpages.com/mouse.htm
Human ApoE
gene
Human Presenilin
gene
Figure 1. Development of the Transgenic Mouse Model of Alzheimer's Disease.
The transgene consists of the human APP gene containing a mutation causing a rare form of early-onset familial Alzheimer's disease (Val717Phe).
The transgene, whose expression is driven by the platelet-derived growth factor (PDGF) promoter, is microinjected into mouse eggs and implanted in a
pseudopregnant female mouse. After the progeny are screened for the presence of the transgene, they are bred and their offspring are analyzed for pathologic
features characteristic of Alzheimer's disease. The brains of the transgenic PDAPP (PDGF promoter expressing amyloid precursor protein) mice have abundant
-amyloid deposits (made up of the A peptide), dystrophic neurites, activated glia, and overall decreases in synaptic density.
From NEJM Volume 332:1512-1513
From McGowan, Erikson & Hutton (2006), Trend in Genetics, 22: 281-289.