21 Multifactorial Inheritance

Question 1

What does a polygenic trait refer to?

Answer 1

A trait that is the result of many genes

Question 2

What traits are usually polygenic?

Answer 2

Quantitative traits ie. BP, height and weight

Question 3

What type of distribution is seen for polygenic traits?

Answer 3

Bell curve, no matter the number of genes and alleles

Question 4

What other factor is significant for polygenic traits?

Answer 4

Environment

Question 5

What does the liability distribution model define?

Answer 5

A point on a polygenic distribution curve where a disease state is present. This point is considered the threshold of liability

Question 6

What is an example of varying threshold of liabilities?

Answer 6

Pyloric stenosis is classic in which the threshold of liability is far lower in males than females

Question 7

How are recurrent risks derived for multifactorial diseases?

Answer 7

Non mendelian in inheritance, must derive risk from empirical observation and only serves as an estimate

Question 8

What are the five increasing recurrence risks relative to the proband? (originator of pedigree study)

Answer 8

More than 1 affected family // proband highly affected // proband is of less affected sex // much higher the closer the relationship // risk to siblings and offspring is sqrt of population risk

Question 9

What are the two contributing factors increasing single gene trait complexity?

Answer 9

Locus heterogeneity and background effects

Question 10

What are two methods to determine the role of environment vs genetics for a specific trait?

Answer 10

Twin and adoption studies

Question 11

What are the categorization of twin pairs?

Answer 11

Concodant if both affected and discordant if only one affected

Question 12

How are twin studies interpreted based on qualitative and quantitative traits?

Answer 12

Concordance rate for qualitative and intraclass correlation for quantitative traits

Question 13

How is heritability calculated using twin studies?

Answer 13

Heritability is twice the difference between the monozygotic and dizygotic concordance rates

Question 14

What forms the basis of adoption studies?

Answer 14

Inheritance of a trait in adopted vs biological children and note if occurrence is the same rate = environment

Question 15

What are phenocopies?

Answer 15

A possibly environmental trait without an associated genetic cause

Question 16

What are quantitative trait loci?

Answer 16

Areas of the genome where genes associated with a specific polygenic trait are located

Question 17

How are QTL’s found?

Answer 17

Genome scan>alleles at each loci involved with trait>screen for candidate genes

Question 18

What is an alternate more cost effective determining method to finding QTLs?

Answer 18

Using siblings with the same disorder as they must share genes causing the effect as well as 50% of genes in general. Optimal if third sibling without disorder can be used.

Question 19

What are the three most common multifactorial disorders?

Answer 19

Heart disease, hypertension and diabetes

Question 20

How does family and genetics factor into heart failure?

Answer 20

Positive history, # affected family, affected females, early onset and Hx of familial hypercholesterolemia all contribute to greater risk

Question 21

What type of disorder is familial hypercholesterolemia and what are some important characteristics?

Answer 21

Autosomal dominant, quantitative trait which presents with double cholesterol, atherosclerosis risk, xanthomas. Homozygotes are much severely affected.

Question 22

What gene is usually affected in familial hypercholesterolemia?

Answer 22

LDLR gene for the LDL receptor

Question 23

What are the classes of LDLR mutations from Class I-V

Answer 23

Starting from I = No receptor->degraded/no ER exit->No LDL binding->no migration to cell surface->Cannot unbind LDL/not recycled to surface

Question 24

Why is decreasing cholesterol and fats only lead to a modest effect on hypercholesterolemia?

Answer 24

Cholesterol can also be synthesized

Question 25

What is the best Tx for hypercholesterolemia?

Answer 25

Diet to limit intake, bile binders(cholestyramine) to limit scavenging, statins to inhibit synthesis of cholesterol

Question 26

Other than FH what other cardiac problems are associated with genetics?

Answer 26

half of C. Hypertrophy familial autosomal dominant, ⅓ of Dilated cardiomyopathy mixed/mito dominance, long QT syndrome

Question 27

What genetic mutations are associated with stroke?

Answer 27

Mito MELAS, dementia causing NOTCH3, Clotting inhibitors protein C/S, Leiden Factor V leading to hypercoagulability

Question 28

What are the two specific associated genetic syndromes presenting as HTN and what other general mutated pathways can contribute?

Answer 28

Liddle syndrome(ENaC), Gordon Syndrome(WNK2/4) and mutations of the corticosteroid and RAAS

Question 29

What are the three types of diabetes?

Answer 29

I - early onset, lack of insulin // II - late onset, resistance // MODY - intermediate onset, autosomal dominant

Question 30

What gene mutations are implicated in diabetes type I and how gene related is it?

Answer 30

HLA DR3/4 and VNTR at 5’ end of insulin gene, 50% concordance

Question 31

What gene mutations are implicated in diabetes type II and how gene related is it?

Answer 31

Calpain-10 exacerbated by PPAR-g mutations, 97% concordance, risk increased exponentially by poor diet/exercise

Question 32

What gene mutations are implicated in MODY?

Answer 32

Glucokinase, HNF, IPF and NEUROD1 = all transcription factors responsible for pancreatic development and insulin regulation

Question 33

What genes are possibly associated with Obesity?

Answer 33

Leptin, neuropeptide Y and MCR4

Question 34

Why is simply providing leptin to humans usually not effective at reversing obesity?

Answer 34

Most are simply resistant and not deficient

Question 35

What autosomal dominant disorders can result in Alzheimers?

Answer 35

Gain of function for Presenilis or mutation of APP