Multifactorial Disease
Medical Genetics
Major gene & Minor gene
Additive effect & Additive gene
Polygenic inheritance
Multifactorial inheritance
Multifactorial traits are those
which result from an interaction
between multiple genes and often
multiple environmental factors.
Qualitative Trait
Monogenic trait
120 cm 165 cm
aa AA OR Aa
Height of pituitary dwarfism & normal
Qualitative Trait
Monogenic trait
0~5 % 45~50 % 100 %
aa Aa AA
PAH activity of PKU,carrier & normal
Qualitative Trait
Qualitative trait,genetic traits which are
present or absent,One has the trait or not.
Quantitative Trait
Qualitative trait
Quantitative trait,genetic traits which
are measurable characteristics.
Quantitative Trait
130 140 150 160 170 180 190 200
Height (cm)
80
70
60
50
40
30
20
10
Var
iab
ilit
y Gaussian distributionthe bell-shaped curve
Quantitative Trait
Qualitative trait
Quantitative trait
P the tallest the shortest
AABB A’A’B’B’
F1 the median
AA’BB’
F2 AB AB’ A’B A’B’
AB AABB AABB’ AA’BB AA’BB’
AB’ AABB’ AAB’B’ AA’BB’ AA’B’B’
A’B AA’BB AA’BB’ A’A’BB A’A’BB’
A’B’ AA’BB’ AA’B’B’ A’A’BB’ A’A’B’B’
Quantitative Trait
AABB
AAB’B’
A’A’BB A’A’B’B’
AABB’ A’A’BB’
AA’BB AA’B’B’
AA’BB’
Quantitative Trait
P AABBCC A’A’B’B’C’C’
F1 AA’BB’CC’
Total
0’ 1’ 2’ 3’ 4’ 5’ 6’
1 6 15 20 15 6 1
F2
ABC A’BC AB’C ABC’ A’B’C AB’C’ A’BC’ A’B’C’
ABC
A’BC
AB’C
ABC’
A’B’C
AB’C’
A’BC’
A’B’C’
AABBCC AA’BBCC AABB’CC AABBCC’ AA’BB’CC AABB’CC’ AA’BBCC’ AA’BB’CC’
AA’BBCC A’A’BBCC AA’BB’CC AA’BBCC’ A’A’BB’CC AA’BB’CC’ A’A’BBCC’ A’A’BB’CC’
AABB’CC AA’BB’CC AAB’B’CC AABB’CC’ AA’B’B’CC AAB’B’CC’ AA’BB’CC’ AA’B’B’CC’
AA’BB’CC AA’BBCC’ AABB’CC’ AABBC’C’ AA’BB’CC’ AABB’C’C’ AA’BBC’C’ AA’BB’C’C’
AA’BB’CC A’A’BB’CC AA’B’B’CC AA’BB’CC’ A’A’B’B’CC AA’B’B’CC’ A’A’BB’CC’ A’A’B’B’CC’
AABB’CC’ AA’BB’CC’ AAB’B’CC’ AABB’C’C’ AA’B’B’CC’ AAB’B’C’C’ AA’BB’C’C’ AA’B’B’C’C’
AA’BBCC’ A’A’BBCC’ AA’BB’CC’ AA’BBC’C’ A’A’BB’CC’ AA’BB’C’C’ A’A’BBC’C’ A’A’BB’C’C’
AA’BB’CC’ A’A’BB’CC’ AA’B’B’CC’ AA’BB’C’C’ A’A’B’B’CC’ AA’B’B’C’C’ A’A’BB’C’C’ A’A’B’B’C’C’
Characteristics of
Polygenic Inheritance
2,Hybridization of F1 of intermediate type
3,Random hybridization
20
1515
66
1 1
0’ 1’ 2’ 3’ 4’ 5’ 6’
1,Hybridization of two extreme variant (Homozygote)
1,Most of common diseases and common
congenital malformation,incidence ＞
1/1000
2,Caused by the genetic basis and tend to
aggregate in families.
3,Resulting from the impact of multiple
genes,recurrence rate ≈ 1％ ～ 10％ 。
Characteristics of
Polygenic Disease
Susceptibility,characterize the genetic factors
that affect the probability of
multifactorial disorder.
Liability,be a measure of all of the factors that
affect the probability of multifactorial
disorder,both genetic (innate) and
environmental.
Threshold Theory
60
50
40
30
20
10
Low High
Liability
Va
ria
bi
lit
y Threshold
Affected
Threshold Theory
σ
Gaussian Distribution
μ
68.28 %
95.46 %
99.74 %
Heritability
Heritability (H,h2)
Measure (%) of the proportion of the
total phenotypic variance that is due to
the genetic basis.
If H is high —— phenotypic variation is
largely genetic
If H is low —— phenotypic variation is largely
environmental
1,General population VS Relatives of patient
2,Relatives of control VS Relatives of patient
h2＝ br b,regression coefficientr,coefficient of relationship
b ＝ Xg— Xra
g
b ＝ Pc(Xc— Xr)a
c
Heritability
Investigation of 100 Families of
Interatrial Septal Defect
First degree relative Total Affected
Parents 200 7
Sibs 279 10
Children 190 5
Total 669 22
X v alue a nd a v alue o f po pulatio n a nd a ffec ted
T ota l Affe cte d I ncide nce X v alue a va lue
Popula tion — — 0.001 3.090 3.367
Affe cte d 669 22 0.033 1.838 2.231
Estimate of Heritability
b ＝ Xg— Xra
g
b ＝ 3.090－ 1.8383.367 ＝ 0.372
h2＝ br h2＝ 0.3721/2 ＝ 0.744
F irst degree relativ e T otal P atie n t I ncidence P val ue X val ue a val ue
Con tr ols 1473 6 0.004 0.996 2.652 2.962
Affecte d 1437 36 0.025 0.975 1.960 2.338
b ＝ 0.996(2.652－ 1.960)2.962 ＝ 0.233
h2＝ br h2＝ 0.2331/2 ＝ 0.466
b ＝ Pc(Xc— Xr)a
c
Investigation of First Degree Relative of
the Controls and Kidney Stone Patients
Holgiger formula
Monozygotic twin,MZ
Dizygotic twin,DZ
CMZ－ CDZ
h2 ＝ 1－ C
DZ
Estimate of Heritability
Aggregate but do not segregate in families.
But the pedigree do not exhibit simple Mendelian
expectations.
Inheritance Characteristics of
Polygenic Disease
First degree relatives have the same risk of
affected.
Inheritance Characteristics of
Polygenic Disease
Aggregate but do not segregate in families.
Contrast this with AD,where the recurrence risk
falls off proportionately with the degree of
relationship.
Risk of affected relatives falls off very quickly
with the degree of relationship.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Inheritance Characteristics of
Polygenic Disease
But only slightly when compared to rare AR diseases.
Consanguinity also increases the probability of
an affected child for a multifactorial trait.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Risk of affected relatives falls off very quickly
with the degree of relationship.
Inheritance Characteristics of
Polygenic Disease
Variation among populations.
Consanguinity also increases the probability of
an affected child for a multifactorial trait.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Risk of affected relatives falls off very quickly
with the degree of relationship.
Inheritance Characteristics of
Polygenic Disease
Estimate of Recurrence Risk
Edward formula
0.2 0.4 0.6 0.8 1 2 4 6 8 10
Incidence of population (%)
40
20
10
8
6
4
2
1
0.8
0.6
0.4
0.2
0.1
In
cid
en
ce
of
fir
st
de
gr
ee
re
lat
ive
(%
)
100
90
80
70
60
50
40
30
20
10
0
Incidence ≈ 0.1%～ 1%
Heritability ≈ 70％～ 80％
f = P
Recurrence risk increases with the number
of affected in a family.
Estimate of Recurrence Risk
Edward formula
Affected parents 0 1 2
Population Heritability Affected sibs Affected sibs Affected sibs
incidence (％ ) 0 1 2 0 1 2 0 1 2
100 1 7 14 11 24 34 63 65 67
1.0 80 1 6 14 8 18 28 41 47 52
50 1 4 8 4 9 15 15 21 26
100 0.1 4 11 5 16 26 62 63 64
0.1 80 0.1 3 10 4 14 23 60 61 62
50 0.1 1 3 1 3 9 7 11 15
Recurrence risk &
the number of affected
Recurrence risk increases with severity of
the defect.
Carter-effect
Estimate of Recurrence Risk
Recurrence risk increases with the number
of affected in a family.
Edward formula
Threshold
♀♂
Congenital Stenosis of Pylorus
0.29%0.81%1.28%6.67%11.48%22.95%n=149
2/6946/7451/784/607/6214/61Female
0.29%0.57%0.47%2.16%2.55%6.42%n=281
3/10436/10611/2135/2317/27419/296Male
Female
cousin
Male
cousinDaughtersSons Nephew Niece
Congenital Stenosis of Pylorus
Congenital Dislocation of Hip Joint
Threshold
♀ ♂
Back
Congenital Dislocation of Hip Joint
Medical Genetics
Major gene & Minor gene
Additive effect & Additive gene
Polygenic inheritance
Multifactorial inheritance
Multifactorial traits are those
which result from an interaction
between multiple genes and often
multiple environmental factors.
Qualitative Trait
Monogenic trait
120 cm 165 cm
aa AA OR Aa
Height of pituitary dwarfism & normal
Qualitative Trait
Monogenic trait
0~5 % 45~50 % 100 %
aa Aa AA
PAH activity of PKU,carrier & normal
Qualitative Trait
Qualitative trait,genetic traits which are
present or absent,One has the trait or not.
Quantitative Trait
Qualitative trait
Quantitative trait,genetic traits which
are measurable characteristics.
Quantitative Trait
130 140 150 160 170 180 190 200
Height (cm)
80
70
60
50
40
30
20
10
Var
iab
ilit
y Gaussian distributionthe bell-shaped curve
Quantitative Trait
Qualitative trait
Quantitative trait
P the tallest the shortest
AABB A’A’B’B’
F1 the median
AA’BB’
F2 AB AB’ A’B A’B’
AB AABB AABB’ AA’BB AA’BB’
AB’ AABB’ AAB’B’ AA’BB’ AA’B’B’
A’B AA’BB AA’BB’ A’A’BB A’A’BB’
A’B’ AA’BB’ AA’B’B’ A’A’BB’ A’A’B’B’
Quantitative Trait
AABB
AAB’B’
A’A’BB A’A’B’B’
AABB’ A’A’BB’
AA’BB AA’B’B’
AA’BB’
Quantitative Trait
P AABBCC A’A’B’B’C’C’
F1 AA’BB’CC’
Total
0’ 1’ 2’ 3’ 4’ 5’ 6’
1 6 15 20 15 6 1
F2
ABC A’BC AB’C ABC’ A’B’C AB’C’ A’BC’ A’B’C’
ABC
A’BC
AB’C
ABC’
A’B’C
AB’C’
A’BC’
A’B’C’
AABBCC AA’BBCC AABB’CC AABBCC’ AA’BB’CC AABB’CC’ AA’BBCC’ AA’BB’CC’
AA’BBCC A’A’BBCC AA’BB’CC AA’BBCC’ A’A’BB’CC AA’BB’CC’ A’A’BBCC’ A’A’BB’CC’
AABB’CC AA’BB’CC AAB’B’CC AABB’CC’ AA’B’B’CC AAB’B’CC’ AA’BB’CC’ AA’B’B’CC’
AA’BB’CC AA’BBCC’ AABB’CC’ AABBC’C’ AA’BB’CC’ AABB’C’C’ AA’BBC’C’ AA’BB’C’C’
AA’BB’CC A’A’BB’CC AA’B’B’CC AA’BB’CC’ A’A’B’B’CC AA’B’B’CC’ A’A’BB’CC’ A’A’B’B’CC’
AABB’CC’ AA’BB’CC’ AAB’B’CC’ AABB’C’C’ AA’B’B’CC’ AAB’B’C’C’ AA’BB’C’C’ AA’B’B’C’C’
AA’BBCC’ A’A’BBCC’ AA’BB’CC’ AA’BBC’C’ A’A’BB’CC’ AA’BB’C’C’ A’A’BBC’C’ A’A’BB’C’C’
AA’BB’CC’ A’A’BB’CC’ AA’B’B’CC’ AA’BB’C’C’ A’A’B’B’CC’ AA’B’B’C’C’ A’A’BB’C’C’ A’A’B’B’C’C’
Characteristics of
Polygenic Inheritance
2,Hybridization of F1 of intermediate type
3,Random hybridization
20
1515
66
1 1
0’ 1’ 2’ 3’ 4’ 5’ 6’
1,Hybridization of two extreme variant (Homozygote)
1,Most of common diseases and common
congenital malformation,incidence ＞
1/1000
2,Caused by the genetic basis and tend to
aggregate in families.
3,Resulting from the impact of multiple
genes,recurrence rate ≈ 1％ ～ 10％ 。
Characteristics of
Polygenic Disease
Susceptibility,characterize the genetic factors
that affect the probability of
multifactorial disorder.
Liability,be a measure of all of the factors that
affect the probability of multifactorial
disorder,both genetic (innate) and
environmental.
Threshold Theory
60
50
40
30
20
10
Low High
Liability
Va
ria
bi
lit
y Threshold
Affected
Threshold Theory
σ
Gaussian Distribution
μ
68.28 %
95.46 %
99.74 %
Heritability
Heritability (H,h2)
Measure (%) of the proportion of the
total phenotypic variance that is due to
the genetic basis.
If H is high —— phenotypic variation is
largely genetic
If H is low —— phenotypic variation is largely
environmental
1,General population VS Relatives of patient
2,Relatives of control VS Relatives of patient
h2＝ br b,regression coefficientr,coefficient of relationship
b ＝ Xg— Xra
g
b ＝ Pc(Xc— Xr)a
c
Heritability
Investigation of 100 Families of
Interatrial Septal Defect
First degree relative Total Affected
Parents 200 7
Sibs 279 10
Children 190 5
Total 669 22
X v alue a nd a v alue o f po pulatio n a nd a ffec ted
T ota l Affe cte d I ncide nce X v alue a va lue
Popula tion — — 0.001 3.090 3.367
Affe cte d 669 22 0.033 1.838 2.231
Estimate of Heritability
b ＝ Xg— Xra
g
b ＝ 3.090－ 1.8383.367 ＝ 0.372
h2＝ br h2＝ 0.3721/2 ＝ 0.744
F irst degree relativ e T otal P atie n t I ncidence P val ue X val ue a val ue
Con tr ols 1473 6 0.004 0.996 2.652 2.962
Affecte d 1437 36 0.025 0.975 1.960 2.338
b ＝ 0.996(2.652－ 1.960)2.962 ＝ 0.233
h2＝ br h2＝ 0.2331/2 ＝ 0.466
b ＝ Pc(Xc— Xr)a
c
Investigation of First Degree Relative of
the Controls and Kidney Stone Patients
Holgiger formula
Monozygotic twin,MZ
Dizygotic twin,DZ
CMZ－ CDZ
h2 ＝ 1－ C
DZ
Estimate of Heritability
Aggregate but do not segregate in families.
But the pedigree do not exhibit simple Mendelian
expectations.
Inheritance Characteristics of
Polygenic Disease
First degree relatives have the same risk of
affected.
Inheritance Characteristics of
Polygenic Disease
Aggregate but do not segregate in families.
Contrast this with AD,where the recurrence risk
falls off proportionately with the degree of
relationship.
Risk of affected relatives falls off very quickly
with the degree of relationship.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Inheritance Characteristics of
Polygenic Disease
But only slightly when compared to rare AR diseases.
Consanguinity also increases the probability of
an affected child for a multifactorial trait.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Risk of affected relatives falls off very quickly
with the degree of relationship.
Inheritance Characteristics of
Polygenic Disease
Variation among populations.
Consanguinity also increases the probability of
an affected child for a multifactorial trait.
First degree relatives have the same risk of
affected.
Aggregate but do not segregate in families.
Risk of affected relatives falls off very quickly
with the degree of relationship.
Inheritance Characteristics of
Polygenic Disease
Estimate of Recurrence Risk
Edward formula
0.2 0.4 0.6 0.8 1 2 4 6 8 10
Incidence of population (%)
40
20
10
8
6
4
2
1
0.8
0.6
0.4
0.2
0.1
In
cid
en
ce
of
fir
st
de
gr
ee
re
lat
ive
(%
)
100
90
80
70
60
50
40
30
20
10
0
Incidence ≈ 0.1%～ 1%
Heritability ≈ 70％～ 80％
f = P
Recurrence risk increases with the number
of affected in a family.
Estimate of Recurrence Risk
Edward formula
Affected parents 0 1 2
Population Heritability Affected sibs Affected sibs Affected sibs
incidence (％ ) 0 1 2 0 1 2 0 1 2
100 1 7 14 11 24 34 63 65 67
1.0 80 1 6 14 8 18 28 41 47 52
50 1 4 8 4 9 15 15 21 26
100 0.1 4 11 5 16 26 62 63 64
0.1 80 0.1 3 10 4 14 23 60 61 62
50 0.1 1 3 1 3 9 7 11 15
Recurrence risk &
the number of affected
Recurrence risk increases with severity of
the defect.
Carter-effect
Estimate of Recurrence Risk
Recurrence risk increases with the number
of affected in a family.
Edward formula
Threshold
♀♂
Congenital Stenosis of Pylorus
0.29%0.81%1.28%6.67%11.48%22.95%n=149
2/6946/7451/784/607/6214/61Female
0.29%0.57%0.47%2.16%2.55%6.42%n=281
3/10436/10611/2135/2317/27419/296Male
Female
cousin
Male
cousinDaughtersSons Nephew Niece
Congenital Stenosis of Pylorus
Congenital Dislocation of Hip Joint
Threshold
♀ ♂
Back
Congenital Dislocation of Hip Joint
