Multifactorial Inheritance (Fingerlin L1)

Question 0

What is a polygenetic or multigenetic effect?

Answer 0

Collective effect of multiple loci along the genome that either raises or lowers an individuals susceptibility to disease; combined with environmental exposures.

Environmental exposures may trigger, accelerate, exacerbate or protect against the disease

Question 1

What is a multifactorial (complex) inheritance pattern?

Answer 1

A disease that “runs in families” but is due to complex interactions between genetics and environmental factors.

Question 2

What is a modifier gene?

Answer 2

Gene whose action can affect the occurrence or severity of an otherwise Mendelian disease.

Question 4

Since we do not understand the underlying mechanisms of gene-gene and gene-environment interactions for most complex disorders, what do clinicians rely on to assess risk for a patient?

Answer 4

Empirically derived risk figures

Question 4

Concordant vs. Discordant?

Answer 4

Concordant = two related individuals in a family have the same disease

Discordant = only one member of a pair of relatives has the disease

Question 5

A hallmark feature of complex inheritance is __________; however ________ does not necessarily imply genetic contribution to a disease.

Answer 5

familial aggregation (affected individuals cluster in families)

familial aggregation

Question 6

What is Relative Risk (lambda_r)? How is the value of rel. risk interpreted?

What is lamba_s?

Answer 6

Lambda_r = (prevalence of disease in affected person’s relatives) / (prevalence of disease in general population)

Count sick relatives. Divide by sick people in general pop.

Larger lambda_r = greater familial aggregation
lambda_r = 1 means person’s risk is same as general pop. risk
lambda_s uses siblings only for numerator value
See table p. 153 for appropriate values

Question 7

Other than Relative Risk, what is another way to asses familial aggregation?

Answer 7

Case control study.
Frequency of disease in family (positive family history) is compared to control group (matched for age, ethnicity)

Subjct to bias such as ascertainment bias = accurate reporting of disease

Question 8

Biases, causation issues generally associated with case control studies?

Answer 8

ascertainment bias = likelihood of relatives to report disease
recall bias = not reporting due to not knowing of/about the disease

association does not necessarily imply causation
e.g. ethnicity vs. diet - may not know which is the real causative factor

Question 9

Disease concordance less than 100% in monozygotic twins is strong evidence that nongenetic factors such as ___________ play a role in the disease.

Answer 9

environmental influences such as exposure to infection or diet
other effects such as somatic mutations, aging, differential X-inactivation in one female twin compared to the other

Question 10

In type 1 diabetes, what are the following values?

1. Risk in general population?
2. Risk to sibs of type 1 diabetes pt?
3. lambda_s for a sibling of a type 1 diabetes pt?

Answer 10

1. 0.4%
2. 6%
3. lambda_s = 6/0.4 = 15

Question 11

What are the 4 characteristics of a complex inheritance disease? (book p. 159)

Answer 11

1. Genetic component but not “single-gene” and not simple mendelian pattern
2. Familial Aggregation
3. Discordance in disease phenotype despite same predisposing allele among relatives.
4. Commonality of disease drops off as relatives become more “distant”. Ex: high concordance btwn MZ or DZ twins. low concordance btwn distant cousins

Question 12

What are the 4 characteristics of a complex inheritance disease? (Lecture notes p. 1)

Answer 12

1. Familial Aggregation
2. Not simple Mendelian inheritance pattern
3. Likely due to gene variants and environmental (non-genetic) factors.
4. No simple relationship between allelic variant & trait when considering the whole population.

Question 13

Cystic Fibrosis penetrance and expressivity?

Pancreatic insufficiency?
Degree of pulmonary disease?

Answer 13

penetrance = 100%
expressivity = variable

mutation of specific alleles in CFTR gene are directly related to pancreatic insufficiency
pulmonary disease not directly correlated to specific mutations in CFTR gene. perhaps genetic modifiers elsewhere in the genome have an expressivity effect. ( and some environmental effects)

Question 14

Give some examples (from lecture and text) of multifactorial inheritance traits.

Answer 14

Lecture: some cancers, type 1 diabetes, type 2 diabetes, alzheimer disease, inflammatory bowel disease, schizophrenia, cleft lip/palate, hypertension, rheumatoid arthritis, asthma

Text:  Digenic Retinitis Pigmentosa (gene-gene interaction)
Venous Thrombosis (gene-gene predisposition to hypercoagulability states)
Hirschsprung Disease (p. 162), Anencephaly, spina bifida and other nerural tube closure defects, coronary artery disease

Question 15

What is heritibility (h^2) of a complex inheritance trait?

Answer 15

The proportion of variance in a trait that is due to genetic variation.

Question 16

Characteristics of complex traits from lecture slide?

Answer 16

1. incomplete penetrance
2. variable expressivity
3. heterogeneity - allele and locus
4. presence of phenocopies.

Question 17

Describe the complex inheritance pattern of Digenic Retinitis Pigmentosa

Answer 17

Two rare mutations in two different unlinked genes for photoreceptor proteins (peripherin locus and ROM1 locus) interact.

Heterozygous for one of either mutation = no disease
Heterozygous for both mutations = disease

Deleterious effects of both genes causes cell damage, photoreceptor death, loss of vision

The two proteins interact noncovalently in the photoreceptors so the compound insult leads to disease state. (p 160)

Question 18

In type 1 diabetes up to _______% of the population has one of __________ haplotypes, but incidence of disease is only ____%

Explain.

Answer 18

20%, one of the two highest risk haplotypes
0.4% has disease

Environmental, lifestyle factors?

Question 19

Type 1 diabetes vs. type 2 diabetes.
Which is insulin dependent?
What proportion of cases does each represent?

Answer 19

type 1 insulin dependent (IDDM) 10% of cases

type 2 non-insulin dependent (NIDDM) 88% of cases

Question 20

Explain variable expressivity.

Answer 20

individuals with same allelic variant that do not show the same disease or quantitative phenotype characteristics.

Question 21

Do type 1 and type 2 diabetes display familial aggregation?

Answer 21

yes, but only one of the two types will be present in a given family

Question 22

Type 1 diabetes incidence and age of onset?

Pathology?

Answer 22

1 in 500 (0.2%), lower in African and Asian populations
onset in childhood or adolescence

Autoimmune destruction of Beta cells in the pancreas that normally produce insulin

Question 23

Discuss the two types of allelic heterogeneity.

What example was given in lecture of a disease exhibiting allelic heterogeneity?

Answer 23

1. Different alleles in same gene result in same trait.
2. Different alleles in same gene result in different trait.

Cystic Fibrosis

Question 24

Describe locus heterogeneity.

What example was given in class for locus heterogeneity?

Answer 24

Variants in different genes result in very similar clinical presentation.

Early onset Alzheimer disease. mutations in 3 different genes all result in same clinical presentation of early onset AD. Basically, a mutation any one of the proteins in the pathway leading to alzheimers (see AD vignette) can cause disease.

Question 25

Describe phenocopy.

Answer 25

environmentally caused phenotype (disease) that mimics the genetic version of the trait.

Question 26

What is Thalidomide?

Answer 26

morning sickness medication (pregnant women) that caused limb malformations. the same limb malformations were previously seen from genetic disease, but thalidomide increased the prevalence of the malformations thus mimic-ing the genetic disease.

Question 27

List risk factors for type 2 diabetes
Associations?
Control measures?

Answer 27

increasing age, obesity, physical inactivity, family history, prior gestational diabetes, impaired glucose tolerance (IGT)

associations: high LDL, triglycerides and blood pressure

control often attained with diet and exercise (but not always)

Question 28

What are some pieces of evidence for a genetic component in type 2 diabetes?

Answer 28

1. aggregates in families (early 1900’s)
2. concordance rates for MZ twins twice that for DZ twins
3. 3 to 4 times risk for relatives of type 2 diabetes patients as compared to the risk of the general population.
4. intermediate traits of blood glucose and insulin levels have heritability rates as high as 50%

Question 29

Type 2 diabetes pathogenesis…

Answer 29

Insulin resistance + genetic predisposition + environmental factors

• –> insulin deficiency —> impaired glucose tolerance
• –> type 2 diabetes

Question 30

Cystic fibrosis exhibits 100% penetrance but variable expressivity of ____________ and ___________ involvement.

Answer 30

lung and pancreatic

Question 31

________% of all patients with type ____ diabetes are heterozygous for mutations in the HLA class II locus of the ______.

Answer 31

95% (compared to 50% in the general population)
type 1 diabetes
MHC (major histocompatibility complex)

Question 32

Genetic factors alone do not cause diabetes type 1 because the _________ rate is only _______.

Answer 32

MZ twin concordance rate is only 40%

…but the dizygotic twin concordance rate is 5%