Multifactorial Diseases

Question 1

What ratio is used in studies to determine heritability of a disease?

Answer 1

λ_R - disease frequency among relatives / disease frequency in entire population

higher value = stronger genetic contribution

λ_R = 1 means no genetic background

Question 2

How can the λ_R ratio be measured differently to assess disease “accumulation” within a family?

(And what is the value of this different ratio in different forms of diabetes?)

Answer 2

λ_S - freq. among siblings / frequency in population

MODY = 50 (very heritable)

T1DM = 15

T2DM = 3.5

(bc of higher incidence of T2 overall, but family clustering is actually stronger for T2)

Question 3

What are the terms for investigating heritability among identical twins?

(What can differences btwn mono-/dizygotic twin’s tendencies to share a disease indicate about its heritability?)

Answer 3

Discordance - when twins don’t both have the same diseased/healthy state

Concordance - when twins share the diseased/healthy state

(higher concordance in mono- than dizygotic twins suggests genetic factors)

Question 4

How can environmental factors be investigated in the development of multifactorial disease?

Answer 4

Adoption Studies

if there is strong concordance with adopted parents, environment is likely decisive in disease development

Question 5

What are some environmental factors possibly involved in T1DM development?

(6)

Answer 5

1. Enteroviruses (Coxsackie B)
2. No breastfeeding / early cow milk exposure
3. Low vitamin D intake
4. Stress
5. Gut Microbiome Issues
6. Low Symbiote Exposure

Question 6

How is MODY inherited?

(what genes are involved?)

Answer 6

AD inheritance

glucokinase and hepatocyte nuclear factor (HNF-1/4 alpha)

Question 7

What is a continous vs. a discontinous trait?

Answer 7

continuous - has a scale/spectrum of expression, usually with a normal/Gaussian distribution (ex = height)

discontinous - is either present or absent

Question 8

How do the frequencies of poly-, oligo- and monogenic diseases compare?

Answer 8

poly > oligo > monogenic

Question 9

What is antagonistic pleiotropy?

example?

Answer 9

when a variant is advantageous at one age, but harmful at another

(technically just when one gene controls for >1 trait, and one trait is beneficial, while the other is harmful)

ex: strong inflammatory responses are helpful in young, but harmful in old when inflammatory diseases like atherosclerosis, RA + Alzheimers are more common; TLR4 Asp299Gly SNP > weak Gram(-) response, frequent in centenarians

Question 10

What are some genes with variants related to reduced insulin secretion in T2DM?

+ their mechanisms

Answer 10

• CDKs (AL1/N2A/N2B) - variants can result in decreased B-cell mass
• KCNJ11 - can cause K+ channel closure dysfunctions

Question 11

What are 2 genes with variants related to insulin resistance in T2DM?

+ their mechanisms?

Answer 11

1. FTO - “fat mass and obesity-related gene”, codes for a hypothalamic protein; deficiency contributes to T2DM
2. IRS1 - “insulin receptor substrate 1”, variants > insuling signaling changes > T2DM

Question 12

Pharmacogenomic studies have shown increased efficacy of certain drugs for certain forms of T2DM and MODY.

Which drugs for which forms/gene variants?

Answer 12

• KCJN1/PPARG in T2DM - sulfonylureas + glitazones
• GCK-MODY - diet
• HNF1A-MODY - low dose sulfonylurea

Question 13

How does a continous trait “become” discontinous?

Answer 13

when it passes a certain threshold to produce disease

ex: fasting blood sugar levels are on a continous spectrum, but above a certain point will qualify as DM

Question 14

In multifactorial diseases…

1. how are they related to gender?
2. how at-risk are first-degree relatives of the less-affected gender?
3. how is the concordance rate in mono/dizygotic twins?

Answer 14

• occur more frequently in one gender, but not sex-linked/limited
• first degree relatives of individual of less-affected gender have higher disease risk
• concordance rate in twins contradicts Mendelian proportions

Question 15

In multifactorial diseases…

1. what influence can environmental factors have?
2. how does ethnicity play a role?
3. how does degree-of-relationship affect risk?

Answer 15

1. environment can increase or decrease risk
2. disease occurs more frequently in certain ethnicities
3. risk of affected relatives decreases quickly with degree of relationship

Question 16

In multifactorial diseases…

1. how does inheritance relate to Mendelian inheritance?
2. how does # of affected children affect recurrence risk?
3. how does disease severity affect reccurence risk?
4. how does marriage of relatives affect risk?

Answer 16

1. inheritance is not Mendelian
2. recurrence risk increases with # of affected children
3. recurrence risk increases with disease severity
4. marriage of relatives moderately increases risk

Question 17

What is linkage disequilibrium?

Answer 17

the phenomenon of two alleles being inherited together more frequently than expected

can indicate a genetic marker for given phenotype

Question 18

what is a haplotype?

Answer 18

a group of genes in an organism that are inherited together from a single parent

Question 19

What is an important example of a class of multifactorial diseases affecting intrauterine development?

What are 2 different expressions/severities of these disorders?

What nutrient affects these diseases and (briefly) how?

Answer 19

Neural Tube Defects

can be less severe (spina bifida) or more (anencephaly)

folate (B9) can help prevent NTDs because of its importance in methylation (THF cycle + SAMe)