Transcript C303, Teaching Building 2015/09 Genetic Susceptibility（易感性）

复杂疾病的遗传学
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: C303, Teaching Building
2015/09
Genetic Susceptibility（易感性）
• An inherited predisposition to a
disease or disorder which is not due
to a single-gene cause and is usually
the result of a complex interaction of
the effects of multiple different genes,
i.e. polygenic inheritance.
遗传因素和环境因素在疾病中的作用
健康 / 疾病 = 基因 + 环境因素
单基因疾病
致病基因
多因子疾病
外伤
易感基因
环境
基因
血友病 大肠癌 老年痴呆 中风 心血管疾病
肺癌
侏儒 乳腺癌
糖尿病
皮肤癌
哮喘
交通意外
Why study the genetics of common
diseases?
• Understanding the underlying genetics
will lead to understanding the causes,
which may lead to better and more
specific therapies
• Identification of the responsible genes
helps to identify those who are at risk
in families and in the population,
allowing individualized health
assessment and targeted prevention
How to Determine the Genetic Components
of Complex Diseases?
• Family, twin and adoption studies（家系、双生子
和寄养子分析）
• Segregation analysis（分离分析）
• Linkage analysis（连锁分析）
• Association studies and linkage disequilibrium
（关联研究和连锁不平衡分析）
• Identification of DNA sequence variants
conferring susceptibility（鉴定易感基因的突变）
• Trait: Any detectable phenotypic property or
character.
• Qualitative trait（质量性状）: A genetic disease
trait that either present or absent. The pattern of
inheritance for a qualitative trait is typically
monogenetic, which means that the trait is only
influenced by a single gene.
• Quantitative trait（数量性状） : are measurable
characteristics such as height, blood pressure,
serum cholesterol, and body mass index. A
quantitative trait shows continued variation under
the influence of many different genes.
Quantitative trait:Normal distribution
•
•
•
•
•
•
•
Height
Weight
Shape
Color
Blood pressure
metabolic activity
reproductive rate
Polygenes: small-but-equal effect
QTL (quantitative trait loci)
Successive Approximations to a Gaussian
Distribution（逐次逼近正态分布）: QTL
Liability（易患性）
• A concept used in disorders which
are multifactorially determined to
take into account all possible
causative factors.
threshold：
阈值
Familial aggregation（家族聚集性）:
Affected individuals tend to cluster in families.
prevalence（患病率） of the disease in
a relative “r” of an affected person
lr= --------------------------------------------------population prevalence of the disease
• The higher the familial aggregation, the larger
the lr.
• If lr = 1, then the relative is at no greater risk
than anyone in the general population.
Twin studies suffer from many limitations
• Monozygotic (MZ。单卵双生子) twins
are genetically identical clones and
should always be concordant (both the
same.一致性) for any genetically
determined character.
• Dizygotic (DZ。两卵双生子) twins share
half their genes on average, the same as
any pair of sibs（同胞对）.
Genetic Differences between Identical Twins
• All individuals, even MZs, differ in:
– their repertoire（库）of antibodies and
T-cell receptors (because of epigenetic
rearrangements and somatic cell
mutations);
– somatic mutations in general
– the numbers of mitochondrial DNA
molecules (epigenetic partitioning);
– the pattern of X inactivation, if female.
Genetic analysis of quantitative traits
• Correlation（相关）:
• Heritability（遗传率）:
Correlation is a statistical measure of the degree
of association of variable phenomena (a measure
of the degree of resemblance or relationship
between 2 parameters).
Coefficient of correlation (r)
• Positive correlation（正相关）: r>1
• No correlation: r=0
• Negative correlation（负相关）: r<1
Heritability (h2)遗传率: The proportion of
the total variation of a character
attributable to genetic as opposed to
environment factors.
CMZ -- CDZ
• h2 = ----------------------100 -- CDZ
• If cMZ >> cDZ then h2 is high (approaches 1)
• If cMZ = cDZ then h2 is low (approaches 0)
[c = concordance（一致性）]
Heritability (h2) for Various Diseases
Trait or Disease
Concordance Rate
MZ twins
DZ twins
Heritability
Alcoholism
Autism
Cleft lip/palate
Diabetes, type 1
Diabetes, type 2
Measles
Schizophrenia
0.6
0.92
0.38
0.35-0.5
0.7-0.9
0.95
0.47
0.6
>1
0.6
0.6-0.8
0.9-1.0
0.16
0.7
0.3
0.0
0.08
0.05-0.1
0.25-0.4
0.87
0.12
Mendelian Forms of Common Complex Diseases
Common Disease
Mendelian Subtype
Atherosclerosis
Breast cancer
Familial hypercholesterolemia
Familial breast/ovarian cancer
Amyotrophic lateral
Familial ALS
Sclerosis
Parkinson disease
Alzheimer disease
Hypertension
Involved Gene
LDL receptor (LDLR)
BRCA1, BRCA2
Superoxide dismutase (SOD1)
Familial Parkinson disease
-synuclein
Familial AD
PS1, PS2, APP
Liddle syndrome
Renal sodium channel (SCNN1B)
Spectrum of Complexity for Common
Diseases: From “Simple” to Complex
Alzheimer disease (AD)
• Complex genetic contributions to AD
may come from:
– One or more incompletely penetrant genes
that act independently;
– Multiple interacting genes; or
– Combination of genetic and environmental
factors
Spectrum of Complexity for Common
Diseases: From “Simple” to Complex
Alzheimer disease (AD)
• Familial AD
– Approximately 10% of patients have a
monogenic form of AD with highly
penetrant, age-related, autosomal dominant
inheritance
– Presents earlier than typical AD: as early as
3rd decade (20s) compared with 7th-9th
decades for typical AD
– Three genes: PS1, PS2, APP
Even “Sporadic” AD May Have a
Genetic Component
• Apolipoprotein E (APOE)
– Protein component of LDL particle
– Constituent of amyloid plaques in AD
– Three alleles: 2, 3, 4
•
•
•
•
4/4: >90% show AD by age 80
2/3: <10% show AD by age 80
4/- : 25-50% show AD by age 80
Environmental factors also involved
– Association between presence of 4 allele and AD
following head trauma is seen in professional boxers
Genetic Testing for
APOE Genotypes
• Testing asymptomatic（无症状） individuals
for 4 remains controversial（争论）
– Poor predictive value（预测值）
– No effective therapeutic intervention（治疗干预措
施） available to prevent onset（发病）
• Available through direct-to-consumer
marketing（面向消费者的市场）
CNVs are common in all genomes surveyed …
• Blue
= pathogenic
• Red = deletion
• Green = duplication
Genetic mapping of complex traits
• Linkage analysis（连锁分析）
• Association studies（关联研究）
Genetic mapping of complex traits
Linkage analysis: genome scan（全基因组扫描）
which analyzes the disease pedigrees using
hundreds of polymorphic markers (SNP)
throughout the entire genome.
L (θ)
• Lods (log odds score): Z(θ) = log[------------ ]
L (1/2)
Lod score (z)
• A measure of the likelihood of genetic linkage
between loci.The log (base 10) of the odds that
the loci are linked (with recombination θ) rather
than unlinked.
• For mendelian characters a lod score greater
than +3 is evidence of linkage;one that is less than
–2 is evidence against linkage.
Identity by State (IBS) and Identity
by Descent (IBD)
• Both sib pairs share allele A1. The first sib pair
have two independent copies of A1 (IBS but not
IBD); the second sib pair share copies of the same
paternal A1 allele (IBD). The difference is only
apparent if the parental genotypes are known.
Sib Pair Analysis
(A)By random segregation sib pairs share 0, 1 or 2 parental
haplotypes 1/4, 1/2 and 1/4 of the time, respectively.
(B) Pairs of sibs who are both affected by a dominant condition
share one or two parental haplotypes for the relevant
chromosomal segment.
(C) Pairs of sibs who are both affected by a recessive condition share
both parental haplotypes for the relevant chromosomal segment.
Affected sibling-pair（患病同胞对）
analysis
Suggested Criteria for Reporting Linkage
Category of
linkage
Expected No. of
occurrences by
chances in a whole
genome scan
Range of
approximate p
value
Range of
approximate lod
scores
Suggestive
1
7 x 10-4 – 3 x 10-5
2.2 - 3.5
Significant
0.05
2 x 10-5 – 4 x 10-7
3.6 - 5.3
Highly
significant
0.001
<3 x 10-7
>5.4
Confirmed
0.01 in a search of a
candidate region
that gave significant
linkage in a previous
independent study
Lod score: 3.6 for IBD testing of affected sib pairs, 4.0 for IBS
•Given that the loci are truly linked, with recombination fraction q, the likelihood
of a meiosis being nonrecombinant is 1 - θ and the likelihood of it being
recombinant is θ.
•If the loci are in fact unlinked, the likelihood of a meiosis being either
recombinant or nonrecombinant is 1/2.
Family A
There are five recombinants and one nonrecombinant.
The overall likelihood, given linkage, is (1 - θ)5. θ
The likelihood given no linkage is (1/2)6
The likelihood ratio is (1 - θ)5. θ / (1/2)6
The lod score, Z, is the logarithm of the likelihood ratio.
Family B
II1 is phase-unknown.
If she inherited A1 with the disease, there are five nonrecombinants and one
recombinant.
If she inherited A2 with the disease, there are five recombinants and one
nonrecombinant.
The overall likelihood is 1/2 [(1 - θ)5. θ / (1/2)6] + 1/2 [(1 - θ). θ 5 / (1/2)6]. This allows
for either possible phase, with equal prior probability.
The lod score, Z, is the logarithm of the likelihood ratio.
Family C
At this point nonmasochists turn to the computer.
Genome-wide scanning: autozygosity mapping
Positional cloning（定位克隆）
• Disease mapping
- chromosome deletion mutation
- linkage analysis
• Fine mapping
• Candidate genes
- pathogenic mutation
screening
- functional assay
Another method combines genome scanning
and the use of animal models
Population Associations
• The low success rate of linkage studies for cx traits
in the 1990s suggested that many of the
susceptibility factors must be relatively weak,
highly heterogeneous, or both.
• Rather than studying affected relatives, association
studies seek populationwide associations between a
particular condition and a particular allele or
haplotype somewhere in the genome.
Risch N, Merikangas K. The future of genetic studies
of complex human diseases. Science. 1996; 273:1516.
Population Associations
• Association is simply a statistical statement about the cooccurrence of alleles or phenotypes.
HLA-DR4, 36% UK / 78%, rheumatoid arthritis
• A population association can have many possible causes,
not all of which are genetic.
Direct causation:
An epistatic effect:
Population stratification: HLA*A1 and
Type I error: false positives
Linkage disequilibrium (LD):
Association is quite different from linkage, except
where the family and the population merge
• Linkage is a specific genetic relationship
between loci (physical sites on the cs)
• Association is a relation between specific alleles
and/or phenotypes.
• Linkage does not of itself produce any
association in the general population. Linkage
creates association within families, but not
between unrelated people.
Genome-Wide Association Studies (GWAS)
Association studies depend on
linkage disequilibrium (LD)
• The occurrence together of 2 or more alleles
at closely linked loci more frequently than
would be expected by chance. → allelic
association
• EMLD
(http://request.mdacc.tmc.edu/qhuang/
Software/pub.htm)
• D’:0（no LD）~±1 (complete association)
SNP: A change in which a
single base in the DNA
differs from
the usual base at that
position.
Millions of SNP's have been
cataloged in the human
genome. Some SNPs such
that which causes sickle cell
are responsible for disease.
Other SNPs are normal
variations in the genome.
Haplotype
• A group of alleles in coupling at
closely linked loci, usually
inherited as a unit.
Haplotype（单倍型）
Tag SNPs（标记SNP）
• A select, minimal subset of all the SNPs in
a genomic region, chosen because they
are in linkage disequilibrium with one
another in the population. Tag SNPs are
useful because they form a minimum set
of SNPs whose alleles constitute
haplotypes capable of representing all the
common haplotypes in that region.
HapMap: A set of haplotypes, defined by tag
SNPs, distributed throughout the genome, used
for association studies.
Measures of LD（连锁不平衡）
• If 2 loci have alleles A, a and B, b with
frequencies pA, pa, pB and pb → 4 possible
haplotype: AB, Ab, aB and ab; pAB, pAb, paB
and pab.
• If no LD, pAB= pApB and so on. The degree of
departure, D = pABpab – pAbpaB.
• D’=(pAB - pApB )/Dmax (the maximum value
of ∣pAB - pApB∣possible with the given allele
frequencies)
• △2=(pAB - pApB)2/(pApapBpb)
A new
generation
of
genomewide
association
studies
(GWAS) has
finnaly
broken the
logjam in cx
dis
research??
Linkage and Association:
Complementary Techniques
• Linkage operates over a long chromosomal range,
scan the entire genome in a few hundred tests
– 250 ASP, 300 markers = 1.5-3 x 105 tests
– candidate regions impracticably large for
positional cloning
• LD short range phenomenon
– TDT, 300 trios, 25 kb LD = 108 tests
– Need to focus on predetermined candidate
regions by animal models, known gene, or
linkage studies
Difficulties in Identification of DNA Sequence
Variants Conferring Susceptibility to Cx diseases
• No single gene mutation is necessary or sufficient to
cause the disease
– even a true susceptibility allele will be found in some
controls and be absent from some patients.
– The main determinants of susceptibility may be
different in different populations
• No genetic way to identify true determinant among a set
of alleles in a strong LD
• The genetic variants causing susceptibility to common
diseases may not be obvious mutations
– May be SNPs in noncoding regions have small effect
on promoter activity, RNA splicing or mRNA stability.
How to Determine the Genetic Components
of Complex Diseases?
•
•
•
•
Family, twin and adoption studies
Segregation analysis
Linkage analysis
Association studies and linkage
disequilibrium
• Identification of DNA sequence
variants conferring susceptibility
Characteristics of Inheritance of Complex
Diseases
1. Diseases with complex inheritance are not single-gene
disorders and do not demonstrate a simple Mendelian
pattern of inheritance.
2. Diseases with complex inheritance demonstrate familial
aggregation, because relatives of an affected individual are
not likely to have disease-predisposing alleles in common
with the affected person than are unrelated individuals.
3. Pairs of relatives who share disease-predisposing genotypes
at relevant loci may still be discordant for phenotype(show
lack of penetrance) because of the crucial role of
nongenetic factors in disease causation. The most extreme
examples of lack of penetrance despite identical genotypes
are discordant MZ.
4. The disease is more common among the close relatives of the
proband and becomes less common in relatives who are
less closely related. Greater concordance for disease is
expected among MZ verse DZ.