Multifactorial Inheritance Flashcards
Types of variation in genome (DNA variants - a continuum of effect)
Norma variation - eye colour
Difference in response to medication
Influence likelihood of disease
Directly result is genetic condition
How dna sequence variants affect health
Depends on location
Whether they alter essential genes
What is Mendelian inheritance
Caused by mutation in a single nuclear gene
Classical inheritance patterns
- dominant/ recessive
- autosomal/ X linked
What is non Mendelian inheritance
Polygenic (multiple genes)
Multi factorial
Maternal inheritance (mitochondrial)
What is multi factorial inheritance
Combination of changes in multiple genes and environmental factors
Types of Mendelian conditions
– Hypercholesterolaemia
– Marfan syndrome
– Cystic fibrosis
– Sickle cell disease
– Duchenne muscular dystrophy
Examples of multi factorial inherited conditions
More common:
– Coronaryarterydisease
– Diabetes mellitus
– Hypertension
– Cerebrovasculardisease
– Schizophrenia
– Breast and bowel cancers
– Some congenital anomalies
How is genetic component of Mendelian conditions highlighted
By pedigree pattern and recurrence risk
How is genetic component of multi factorial conditions highlighted
by clustering of cases in some families but no obvious inheritance pattern
Aetiology of diseases
Either 100% environmental
Single gene
Or polygenic
Features of Mendelian conditions
Rare
Genetics Simple
Unifactorial
High recurrence risk
Features of multi factorial inheritance
Common
Genetics complex Multifactorial
Low recurrence rate
How to identify genetic and environmental influences
observational studies of the incidence of diseases in different groups of people
Different ways evidence is gathered for observational studies
• Familial clustering
• Twin studies
• Adoption studies
• Population and Migration studies
What are monozygotic twins
Share all genetics and environment
What are dizygotic twins
Non identical
Share same amount of genetics as siblings
Share 50% genes and environment
How can you acquire evidence for genetic/ environmental influences
Comparing concordance of different features btw monozygotic and dizygotic twins
Determining the incidence of a disease in twins helps delineate whether there are genetic and environmental components
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
What is polygenic inheritance
• Polygenic = many genes
• Large number of genetic factors, each making only a small additive contribution to the final phenotype
What are continuous traits
Typically, polygenic inheritance is the basis for continuous traits which follow a normal distribution in the population
displays a range of expression (such as weight, height, etc.) rather than an all-or-none appearance (such as white or red). Continuous traits are usually under polygenic control and subject to substantial environmental influence in expression.
How characters (like eye colour) are regulated
One pair of alleles at a single locus controlling a character
3 possible results
Blend of pair acts as 3rd possibility
How many pairs of alleles needed to build a continuous distribution
Minimum three pairs
What is a liability curve
Normal distribution - Made of genetic and environmental factors
Above threshold liability a person will develop the multifactorial disorder
What is the probability of a relative having a multi factorial inheritance
The probability of a relative having a multifactorial disease is higher because they are more likely to share genes (and environment) in common and so increase their liability
What kind of disease is spina bifida
Multifactorial inheritance
What are bad about epilepsy drugs
Sodium balproate
Risk of developing spina bifida
What do you notice
about the magnitude
of the recurrence risk in other family members for neural tube defects?
As you get further away from affected individual recurrence risk decreases because genetic makeup is less similar
What is the empiric risk
The chance that a disease will occur in a family, based on experience with the diagnosis, past history, and medical records rather than theory
What is the observed recurrence risk after one baby with NTD
4%
Main points of multifactorial disorders
Environmental influences act with a genetic predisposition
Multiple genes with individually small risks often implicated
One organ system affected
What are recurrence risks
- “empiric figures”
- obtained from population studies
the likelihood that a hereditary trait or disorder present in one family member will occur again in other family members
The threshold model of multifactorial inheritance
• The genes (diff genetic makeup) and environmental factors causing a particular multifactorial trait may vary from person to person
What are other models ????
– major gene of large effect acting on multifactorial background
– small number of genes act together
How did we begin to find genes for Mendelian disorders?
• 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
How are the genetic components of common conditions identified?
Genes for common disorders have to be identified through association studies in large populations.
What do association studies rely on
The assumption that people with the same condition share a paticular DNA pattern
What are SNPs
• 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
1/1000 nucleotide
One method of identifying the genetic components of common complex conditions
• Through genome-wide association studies (GWAS)
• Thousands of people
• Test up to 500 000 SNPs in each person by microarray analysis
Comparing SNP frequencies of people with and without disease
Example of how SNPs may affect susceptibility of disease
SNP in GWA affect susceptibility of diabetes
May be location of SNP rather than the SNP itself
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.
How can estimate of susceptibility of disease be given
In future clinical practice, SNPs associated with several genes maybe used together to give estimate of susceptibility – but complex +++!!
What changes may be picked up using a SNP library
• May be direct effect
• May be indirect association / marker for nearby major
genetic influence
Why is genomics informative for clinical practice
Genetic variants can alter drug response and cause adverse effects
New targeted therapies are being developed based on genomic information
Use info to specifically tailor patients drug management
Genomic info can influence health decisions, help people modify risk factors and provide motivation
Types of potential feedback to participants of genomics
Mains findings: all patients receive results about main cond which they were referred for
Additional findings: an opt to receive feedback on selection of know genetic alterations of high clinical sig
Carrier status: parents who planning to have children can opt to find carrier status for genetic diseases
Genomic England?
Government announced plans to sequence the full genomes of up to 100,000 NHS patients:
cancer
rare inherited diseases infectious diseases
The impact of genetic testing on motivation to stop smoking:
Crohn’s disease used as an example
Population Sample (2008 study)
– Shown “their” genetic results
– Expressed motivation to quit
– More motivated if bigger risk
But still showed same behaviour with and without genetic test
What is Crohn’s disease and symptoms
• 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.
To personalise treatment and surveillance we can use genomic information to
- sub classify their disease
- access susceptibility
- predict their response to drugs
- choose best treatment
Common complex disorders: key points
• 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
What increases the chance of having dizygotic twins
Your chances of having Dizygotic twins are increased if you are over 35, take fertility drugs/ have IVF, are taller or overweight and if you have a family history of dizygotic twins on your mothers side (e.g. if you are a twin, your mother had other twins or your grandmother had twins) The chances are also increased 5 times if you have already had one set of dizygotic twins.
The chances for monozygotic twins are completely random
