Multifactorial Disorders

Question 1

Chromosomal and gene disorders affect % of population? single gene disorders? multifactorial diseases?

Answer 1

• -0.38% chromosomal
• -single gene: 2%
• -multifactorial inheritance: 60% of population

Question 2

Contributing vs. Noncontributing Alleles and

Answer 2

• -alleles that contribute to phenotype
• -ex. if 2 genes involved in quantitative trait (height) then that’s 4 potential alleles that could contribute or none at all (0-4) that would be five classes of phenotypes
• -bigger distribution of phenotypes = more bell curve shape
• -noncontributing alleles dont increase height while contributing alleles do
• –applies to disease contributing alleles as well or “liability” (risk of being affected by certain disorder)

Question 3

If more genes are involved in trait/disease, then what?

Answer 3

• -it means there is a lower probability of an offspring inheriting all of none of the contributing alleles
• -which in turn means there is a lower fraction of extreme phenotypes at fringes of bell curve
• -more genes = bigger better bell curve and less affected in extreme areas
• -less genes = flattened bell curve

Question 4

Liability

Answer 4

• -risk of developing a multifactorial disease based on the alleles you inherited
• -does NOT follow normal mendelian pattern

Question 5

Prevalence and Incidence

Answer 5

• -proportion of population affected by disease

- -Incidence: number of new cases in given time by size of the population

Question 6

Analysis of multifactorial diseases follow analysis of quantitative traits, Assumptions?

Answer 6

• -many genes involved in development of disease

- -alleles can be contributing or non-contributing

Question 7

Liability of Distribution and Liability Thershold

Answer 7

• -threshold different for males and females
• -threshold is influenced by environmental factors
• -model explains why recurrence risk is higher than the occurrence risk (contrast to single gene disorder)
• -ex. more affected children born to a couple = higher the assumed number of contributing alleles in parent generation

Question 8

Pyloric Stenosis and Liability of Threshold Example

Answer 8

• -effects 1/200 males and 1/1000 females so low threshold for males and higher threshold for females
• -if affected female then any brothers are much more likely to be affected
• -affected male proband recurrence risk in sisters is lower than if affected female proband has sister

Question 9

Concordance rate

Answer 9

–rate of how often a trait occurs in both members of a pair

Question 10

Dizygotic twins

Answer 10

• -share 50% of DNA

- -no different than siblings that arent twins

Question 11

If concordance in MZ twins is higher than DZ twins then..?

Answer 11

trait has strong genetic component

Question 12

Heritability estimated as

Answer 12

–H(squared) = Concordance MZ - Concordance DZ * 2

Question 13

high heritability value means? low value?

Answer 13

• • high value = the trait is determined predominatly by genetic factors
• -low value = the trait has good chance to be mitigated in environmental changes (diet, etc.)

Question 14

Model-free linkage analysis

Answer 14

• -analyze whole genome for SNP markers in affected families

- -looking for markers that are linked to the disease vs markers in those that arent affected

Question 15

Risk Analysis–familial risk

Answer 15

– Lambda = prevalence of disease in relative (r) of affected person / prevalence in general population

Question 16

2 types of risk

Answer 16

• -first is familial associated: if relative has it what is chance you have it (goes up if relative has it)
• -second is associated w/ genotype

Question 17

Relative Risk–genotype risk

Answer 17

–describes how much more likely a carrier of an allele is to develop disease than non-carrier

Question 18

Characteristics of Multifactorial Disease

Answer 18

• -no mendelian inheritance
• -familial aggregation
• -frequently show incomplete penetrance (due to influence of environment)
• -disease is much more common among close relatives of the affected proband than it is among less related persons

Question 19

Multifactorial Birth Defects:
Risk for general pop.?
One affected 2nd degree relative?
one affected 1st degree relative?
2 affected 1st degree relatives?
3 affected 1st degree relatives?
affected identical twins?

Answer 19

In order listed:

• -0.5%
• -0.7-2% (2-4x)
• -3-4% (6-8x)
• -5-8% (10-16x)
• -9-12% (18-24x)
• -20-30% (40-60x)
• • even though those %’s seem high they still arent near what the rate is for mendelian inherited disorders (25% lowest possible)

Question 20

Ex. of Type 1 Diabetes

Answer 20

• -1/200 incidence

- -concordance rate in MZ twins = 40% (DZ = 4.8%) so disease is not due to genetic factors alone

Question 21

Haplotypes

Answer 21

• -genes passed on as a block

- -ex. HLA genes

Question 22

HLA haplotypes

Answer 22

• -HLA genes are VERY polymorphic
• -each parents has two and transmits one of the two to their child
• -chance of siblings expressing same haplotype = 25%
• -strong contribution to risk for T1D

Question 23

HLA-B haplotypes

Answer 23

–spondyloarthropathy

Question 24

HLA-C haplotypes

Answer 24

–psoriatic arthritis