Wk8 Multifactorial Inheritance

Question 1

What are the effects of DNA sequence variants?

Answer 1

Varying effects on health depending on where they occur and whether they alter the function of essential genes and/or their controlling elements

Question 2

What is Mendelian inheritance?

Answer 2

Caused by mutation in a single nuclear
gene
Classical inheritance patterns:
dominant/recessive autosomal/X-linked

Question 3

What is non-Mendelian inheritance?

Answer 3

Polygenic

Multifactorial (common complex) Maternal inheritance (Mitochondrial)

Question 4

What are some Mendelian conditions?

Answer 4

– Hypercholesterolaemia
– Marfan syndrome
– Cystic fibrosis
– Sickle cell disease
– Duchenne muscular dystrophy

Genetic component highlighted by pedigree pattern and recurrence risk

Question 5

What are some common conditions?

Answer 5

– Coronaryarterydisease
– Diabetes mellitus
– Hypertension
– Cerebrovasculardisease
– Schizophrenia
– Breast and bowel cancers
– Some congenital anomalies

Genetic component suggested by clustering of cases in some families but no obvious inheritance pattern

Question 6

How is evidence gathered?

Answer 6

• Familial clustering
• Twin studies
• Adoption studies
• Population and Migration studies

Question 7

What are the large observational studies of many families?

Answer 7

• Through studying families where there was a multifactorial condition:
probabilities of recurrence for relatives were calculated for general use
by observing the numbers of relatives with the same condition in the studied families

Question 8

What is polygenic inheritance?

Answer 8

• Polygenic = many genes
• Large number of genetic factors, each making only a small additive contribution to the final phenotype
Typically, polygenic inheritance is the basis for continuous traits which follow a normal distribution in the population

Question 9

What is empiric risk?

Answer 9

The chance that a disease will occur in a family, based on experience with the diagnosis, past history, and medical records rather than theory

Question 10

What is the threshold model of multifactorial inheritance?

Answer 10

• The genes and environmental factors causing a particular multifactorial trait may vary from person to person
• Other models:
– major gene of large effect acting on multifactorial background
– small number of genes act together

Question 11

How did we begin to find genes for Mendelian disorders?

Answer 11

• Used families
• Identified by:
– A pedigree pattern indicative of a known mode of inheritance
– The diagnosis of a single gene disorder with a known mode of inheritance

Question 12

How are the genetic components of common conditions identified?

Answer 12

Genes for common disorders have to be identified through association studies in large populations.

Question 13

What are SNPs?

Answer 13

genetic markers used in GWAS

• SNPs are changes of a single base in a particular DNA sequence (in genes or non-coding sequences)
• The physical locations of SNPs are known

Question 14

What is One method of identifying the genetic components of common complex conditions?

Answer 14

• Through genome-wide association studies (GWAS)
• Thousands of people
• Test up to 500 000 SNPs in each person by microarray analysis

Question 15

What are relative risks associated with susceptibility loci?

Answer 15

 Most relative risks associated with particular SNP genotypes are usually low (x 1.1 – x 1.5)
- May increase or decrease risks
- May have variable effects in different combinations!
 Therefore other genes and environmental factors involved.
 In future clinical practice, SNPs associated with several genes maybe used together to give estimate of susceptibility – but complex +

Changes picked up using SNP library:
• May be direct effect
• May be indirect association / marker for nearby major
genetic influence

Question 16

What is the impact of genetic testing on motivation to stop smoking?

Answer 16

Asked 180 Smokers (without Family History of Crohn’s)
• Crohn’s Disease affects the gut.
• It tends to run in families, and is more common in smokers
• Symptoms include
– Abdominal pain
– Diarrhoea
– Fever
– Loss of appetite
– Weight loss
• The symptoms are so serious that some people with Crohn’s disease cannot work or go out.

Question 17

What can we use genomic information for?

Answer 17

• to subclassify their disease
• to asses their susceptibility
• to predict their response to drugs
• to choose the best treatments

Question 18

What are the key points of common complex disorders?

Answer 18

• Both genetic and environmental factors involved in many common conditions.
• Contributions of environment/genetics assessed through – effects of changing environment through migration or adoption
– observed incidence of disease in relatives
– concordance rates in twins
– evaluating association with genetic markers (SNPs) – Whole genome sequencing data / Clinical data
• Genetic factors: an inherited predisposition or due to a combination of genes conferring susceptibility
• To reduce probability that someone will develop a common disorder, need to identify individuals who are genetically susceptible and identify environmental agents involved