Chapter 6Polygenic Inheritance

Polygenic inheritance

Polygenic disease (multifactorial disease)

characteristics

recurrence risk

Outline

Polygenic inheritance

refer to the inheritance of quantitative traits which are influenced by multiple genes at different loci, and environment may be involved.

Genetic factor

Minor gene: a gene that has small observable effects upon the phenotype

Major gene: a gene that has large observable effects upon the phenotype

Codominance

Additive effect

Environmental factor

Qualitative traits vs. Quantitative traits

Qualitative traits (Discontinuous traits) : each trait has two, or a few, very different unambiguous states

Quantitative traits (Continuous traits) : each trait has numerous slightly different variants

Continuous Trait

Discontinuous Trait

Qualitative traits vs. quantitative traits

Polygenic Inheritance

Most traits follow a normal distribution

Polygenic Inheritance

Several loci are involved in the expression of the trait.

There is no dominance or recessive at each of these loci.

The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype.

The environment interacts with the genotype to produce the final phenotype.

Polygenic Inheritance

Homozygous parental pops. : still

show some environmental variation

F1 - intermediate :shows some

variability (environmental)

F2 - much greater variability :

mean is intermediate genetic and

envir.

Polygenic diseases

Common malformation or diseases, PF >0.1%;

Tend to aggregate in families, but the recurrence risks in families often fall in the range of 1% to10% ;

Resulted from an interaction between multiple genes and

often multiple environmental factors

Polygenic Disorders

Congenital Malformations

cleft lip / palate

congenital dislocation of the hip

congenital heart defects

neural tube defects

pyloric stenosis

Talipes

congenital heart disease

Adult Onset Diseases

diabetes mellitus

epilepsy

glaucoma

hypertension

manic depression

Schizophrenia

Asthma

spondylitis ankylopoietica

Susceptibility: recurrence risk is determined

by the genetic basis of a certain polygenic disorder.

Liability: recurrence risk is determined by

genetic and environmental factors simultaneously.

Threshold model is a useful tool for our research

on polygenetic disorders.

The threshold model for multifactorial traits.

Threshold : the minimal gene number leading to polygenic

disorder in a certain environment.

Below the threshold the trait is not expressed.

Individuals above the threshold have the disease .

Threshold model

Mean of population

Normal distribution of liability

95% of values lie within 2 standard deviations of mean;

0.13%

2.3%

16%

The curve for relatives is shifted to the right compared to the general population

the closer the relationship the greater the shift to the right

Threshold model

Phenotypic

variance

Genetic

varianceEnvironmental

variance

VP = VG + VE

Heritability

proportion of the phenotypic variation is due to genes

h2=VG / Vp

Trait Heritability

Clubfoot 0.8

Height 0.8

Blood pressure 0.6

Body mass 0.5

Fingerprint ridge count 0.9

Intelligence 0.5-0.8

Total serum cholesterol 0.6

Heritability

H=1

genes only

H=0environment only

Heritability

h2=b/r

b= (Xg-Xr)/ag

b=p (Xc-Xr)/ac

or

( population study)

( case-control study)

r: coefficient of relationship

Coefficient of Relationship (r)

the fraction of alleles shared by two individuals

A(B) –C(D) :A B

C D

E F

r = 1/2

How about C & D?

Coefficient of Relationship (r)

C

A

D C D

B

1/2 1/2 1/2 1/2

1/2 x 1/2 = 1/4 = fraction of

alleles C & D share from dad

1/2 x 1/2 = 1/4 = fraction of

alleles C & D share from mom

1/4 + 1/4 = 1/2= fraction of alleles C & D share

Coefficient of Relationship (r)

the fraction of alleles shared by two individuals

A(B) –C(D) :A B

C D

E F

r = 1/2

How about C & F?

1/4 + 1/4 = 1/2= fraction of alleles C & D share

C

A

D

F

C D

F

B

1/2 1/2

1/2

1/2 1/2

1/2

1/2 x 1/2 x 1/2 =1/8

= fraction of alleles

C & F share from common

ancestor (A)

1/2 x 1/2 x 1/2 =1/8

= fraction of alleles

C & F share from common

ancestor (B)

1/8 + 1/8 = 1/4 = fraction of alleles C & F share

Coefficient of Relationship (r)

the fraction of alleles shared by two individuals

A(B) –C(D) :A B

C D

E F

r = 1/2

C & F : r = 1/4

E & F ?

C

E

A

D

F

C

E

D

F

B

1/2 1/2

1/21/2

1/2 1/2

1/21/2

1/2 x 1/2 x 1/2 x 1/2 =

1/16 = fraction of alleles

E & F share from common

grandfather

1/2 x 1/2 x 1/2 x 1/2 =

1/16 = fraction of alleles

E & F share from common

grandmother

1/16 + 1/16 = 1/8 = fraction of alleles E & F share

Coefficient of Relationship (r)

r=1/2 1st degree (parent, sib, child)

r=1/4 2nd degree (uncle, niece, grandchild)

r=1/8 3rd degree (first cousin, great-grand)

Characteristics of Polygenic diseases

1. The incidence of the condition is greater in relatives

of the affected individuals than that in general

population, but much less than 25%;

2. The risk is same among the same degree relatives

3. The risk is greatest for the first degree relatives and

decreases rapidly in more distant relatives

4. Consanguinity slightly increases the probability of an affected child for a polygenic disorder

5. Different risk in different race.

ⅠⅡⅢGliability

threshold

Estimating Recurrence Risk

For single gene diseases, the recurrence risk is easy

to calculate.

For polygenic diseases, the recurrence risk must be

derived empirically (i.e. from observations in large

samples).

Empiric risk of cleft palate

Relationship Recurrence Risk

General population 0.1%

First cousin 0.3%

Niece or nephew 0.8%

Child 3.5%

Sibling 4.1%

Identical twin 40.0%

Recurrence risks

Recurrence risks

e.g. Cleft palate, PF=0.16%, h2=76%

??

RR=4%

1. If p is the frequency of a polygenic disease in the

population, the risk for first degree related individuals

is approximately the square root of p, f=√p. (PF=

0.1%-1%; h2= 70-80%)

2.Increase with the number of affected relatives

Recurrence risks

? ? ?

Family A Family B Family C

Family A Family B Family C RR < <

Recurrence Risk for Cleft Lip Depends on Family History

0 1 2

0 0.1 3 34

1 3 11 40

2 8 19 45

No. of

Siblings

Affected

No. of Parents

Affected

3.Increase with the severity of the condition

In multifactorial traits, the more severely affected the individual, the more genes he/she has to transmit, and the higher the recurrence risk.

Recurrence risks

TWO THRESHOLD DISEASES

4.In many multifactorial diseases the two sexes have different probabilities of being affected.

Pyloric stenosis occurs in about 1/200 newborn males but only in about 1/1000 newborn females. This means that there is a double threshold, one for females and one for males, with the female threshold farther from the mean than that for the male. However, since it takes more deleterious genes to create an affected female, she has more genes to pass on to the next generation. Her male offspring are at a relative high risk of being affected when compared to the population risk.

?

Family A

?

Family B

RR:

Family A Family B <

Recurrence risks

Identify the gene of polygenic disorder

Pedigree:

complex segregation analysis

Linkage analysis

Case---control

affected sib pair analysis

SNP association

GWAS( Genomic wide association analysis