Transcript Standardization of pedigree collection

Standardization of
Pedigree Collection
Genetics of Alzheimer’s Disease
Environmental
Factor 1
Environmental
Factor 2
Gene 1
Gene 2
Alzheimer’s Disease
Genetic Approaches to
Gene Identification In
Alzheimer’s Disease
Identifying genes for complex disease



Association
Test candidate gene
Collect sample of
affected and control
subjects
Compare frequency
of a genetic
polymorphism in 2
samples
Affected
Control


Linkage
Test entire genome
Collect families with
multiple affected
members
Linkage vs. Association
 Linkage
 Measures the segregation of alleles and a
phenotype within a family
 Detected over large physical distances
 Association
 Measures preferential segregation of a
particular allele with a phenotype across
families
 Detected over shorter distances
Meiosis and Linkage

Gamete formation
 Meiosis I: Homologous
chromosomes pair

Crossing over occurs
 Genes that are physically
close together are more
likely to be coinherited
 Genes that are physically
far apart on the
chromosome are less
likely to be coinherited
Linkage Approach
 Seeks
to identify, IN FAMILIES,
chromosomal regions that are
consistently transmitted to affected
individuals.
 Identify these regions using ‘markers’
 Find a marker which is ‘linked’ to the
disease
Linkage: Autosomal Dominant
Traditional Linkage Approach

Successful in the identification of
genes for Alzheimer’s disease
 Amyloid precursor protein (APP)
 Presenilin I (PS1)
 Presenilin II (PS2)
Further Genetic Studies

Clearly, most families with Alzheimer’s
disease do not have a clear pattern of
Mendelian inheritance
 Already, one susceptibility gene has been
identified whose alleles can either
increase or decrease the risk of AD
 There are certainly other genes which are
to be identified
How to tackle finding these
other genes?
Genetics of Alzheimer’s Disease
Environmental
Factor 1
Environmental
Factor 2
Gene 1
Gene 2
Alzheimer’s Disease
Linkage in Complex Disease
 Identify
families with multiple affected
members
 Increases the likelihood that genes are
important in disease susceptibility in that
family
 Pattern
of inheritance less certain
 Collect family members to follow
segregation of disease and marker alleles
Identity By Descent (IBD)
Allele
Allele
Allele
Allele
1
2
3
4
AGCTCACACACACACACACACAATCG
AGCTCACACACACACACAATCGTCGA
AGCTCACACACACAATCGTCGACCGC
AGCTCACACACAATCGTCGACCGCGG
Linkage Analysis
 Employ
nonparametric linkage methods
 Identify chromosomal regions that are
preferentially transmitted within a family to
the affected individuals.
 Method is not based on recombination but
on IBD marker allele sharing
Analysis of Affected Relatives
 Look
for chromosomal regions shared in
common by affected relatives in the
same family.
 Presume that affected individuals in the
same family will have some similar
susceptibility genes.
 Look
at patterns across families to
determine if the same chromosomal
region is being shared.
Genome Screen Approach
 Evaluate
the entire genome
 Analyze markers located at regular
intervals throughout the genome
 Identify regions that are consistently
shared by affected relatives
Markers
Association Studies
 Once
a chromosomal region has been
identified which is linked to AD,
additional studies are necessary to
identify the causative gene
 Association
studies typically test for
linkage disequilibrium rather than
linkage.
 Linkage disequilibrium extends over shorter
distances.
 Often employ SNPs.
Association Studies
 Studies
study:
of linkage disequilibrium can
 Transmission of alleles throughout a family
consisting of affected and unaffected
individuals.
 Compare allele frequencies between
affected and unaffected individuals.
 Many
new methods are being
developed to more effectively test for
linkage disequilibrium.
AD Genetics Initiative Goals
 Identification
of genes contributing to
Mendelian forms of AD are very
important.
 Provide insight into important pathways
 Provide potential candidate genes to
examine in non-Mendelian forms of disease
 This
study seeks to identify the genes
contributing to non-Mendelian forms of
AD.
Design of the AD
Genetics Initiative
Appropriate Families for Study
 At
least 2 living siblings with
LOAD (onset > 60 years)
 At
least 1 other living related
family member who :
 Has AD (onset > 50 years)
Or
 Is unaffected (> 60 years)
Appropriate Families for Study
 Who
should be collected in this
family? Why?
I
II
 If parents in generation I are alive,
they should be collected.
 Collection of the parents will allow
allele sharing to be determined more
definitely in studies of the siblings in
generation II.
 More definitive allele sharing
produces more definite linkage results
-> more power to find genes for AD
Appropriate Families for Study
 Who
should be collected in this
family? Why?
I
II
 Collect all siblings in generation II (AD
and non-AD)
 This is particularly important if the
parents in generation I are deceased
 Study allele sharing in generation II.
 Studies can compare allele sharing
among the AD siblings and the
discordant siblings
 Can evaluate linkage disequilibrium.
Deceased Family Members
 Testing
markers in the parents and
offspring of a deceased person makes it
possible to estimate what the individual
must have inherited
Reconstruction
 Estimating
a missing person’s likely
genotype is termed ‘reconstruction’.
 This
is the principal being employed in
the identification of specimens in many
forensic cases.
Power to Reconstruct
 The
power to reconstruct a missing
genotype is dependent on how many
closely related family members can be
sampled.
 The
important people to sample are the
offspring of a deceased, affected
individual.
Appropriate Families for Study
 Who
should be collected in this
family? Why?
I
II
 Offspring of the individuals in generation
II can be important for genetic studies.
 Do any individuals in generation III have
symptoms of memory loss or AD? If so,
collect them.
 Are any of the individuals in generation
III over the age of 60 years?
Longitudinal follow-up of these
individuals may identify new cases of
AD.
Appropriate Families for Study
 Who
should be collected in this
family? Why?
I
II
III
 If any offspring in generation III
are collected, it is important to also
collect both their parents, when
possible.
 The individual in blue is important
when determining which alleles the
offspring in generation III have
inherited from her affected father.
Appropriate Families for Study
 Who
I
II
should be collected in this
family? Why?
 Did anyone in the family have an
autopsy and is tissue still available?
 Collect information about these
individuals and consider obtaining
these materials, if possible.
Who to collect?

A commonly asked question is who
should I collect a blood sample from in
a genetic study?

The answer is all genetically
informative individuals!
Who is genetically informative
 Genetic
analysis seeks to study the
transmission of marker alleles
throughout the family.
 When we can determine the inheritance of
all marker alleles unambiguously, we have
the greatest power to find genes for
disease!
 Unaffected
individuals may be very
important for collection.
Who is genetically informative

Collect affected
individuals

Collect as many
individuals with a
• as are willing to
participate
Who is genetically informative
• Collect
Insert pedigree
with
affected
affected siblings +
individuals
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participate
Which are the best families?
 Families
with the largest number of
affected individuals.
 Strong family history suggests more
genetic.
 Unaffected individuals in families with
many affected individuals are also very
important, particularly if they are examined
clinically.
Who is genetically informative

Collect all affected
individuals

Collect any living
connecting relatives

Collect any
unaffected siblings
Which are the best families?

Cooperative Families
 Families eager to participate in research
will typically complete the study faster.
 Provide annual follow-up information more
easily.
 Assist in research if additional
information/samples are needed.
 Important to remain in contact with
families and provide them with information
about the study
Who to Collect

Collect the parents in generation I,
if available

Collect all siblings in generation II
(affected and unaffected)

Collect any individuals in
generation III with memory loss
II

Collect any individuals in
generation III > 60 years
III

Query for any other affected
cousins, half siblings, aunts,
uncles??
I
When in Doubt??
 Contact
Susan LaRusse who will help
sites identify the critical individuals in
their pedigrees.