© 2009 nhs national genetics education and development centresupporting genetics education for...
TRANSCRIPT
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial conditions
This PowerPoint file contains a number of slides that may be useful for teaching of genetics concepts.
You may use these slides and their contents for non-commercial educational purposes.
More slides will be added to this series shortly.
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
GENETIC ENVIRONMENTAL
Duchenne muscular dystrophy
HaemophiliaOsteogenesis imperfecta
Club footPyloric stenosisDislocation of hip
Peptic ulcerDiabetes
Tuberculosis
PhenylketonuriaGalactosaemia
Spina bifidaIschaemic heart diseaseAnkylosing spondylitis
Scurvy
The contributions of genetic and environmental factors to human diseases
RareGenetics simple
UnifactorialHigh recurrence rate
CommonGenetics complexMultifactorialLow recurrence rate
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Continuous (quantitative) characters
• Polygenic – many genes
• Large number of genetic factors, each making only a small contribution to the final phenotype
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial inheritance
• Inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment
• Clinical clue: One organ system affected
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Family studies of the incidence of cleft lip (± cleft palate)
Anomaly Risk to sibs %
Bilateral cleft lip and palate
5.7
Unilateral cleft lip and palate
4.2
Unilateral cleft lip alone
2.5
The more severe the manifestation of a multifactorial condition, the greater the probability of recurrence
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Some multifactorial conditions have an unequal sex ratio
Condition Sex ratio (males to females)
Pyloric stenosis 5 to 1
Hirschprung disease 3 to 1
Congenital dislocation of hip 1 to 6
Talipes 2 to 1
Rheumatoid arthritis 1 to 3
Peptic ulcer 2 to 1
For some conditions there must be a different threshold for males and females
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Frequency of pyloric stenosis in relativesRelationship Frequency % Increase on general
population risk for same sex
Male relatives of a male patient
5 x10
Female relatives of a male patient
2 x20
Male relatives of a female patient
17 x35
Female relatives of a female patient
1 x70
For a female to be affected with pyloric stenosis, she must have a particularly strong genetic susceptibility
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial inheritance:Factors increasing probability of recurrence in a
particular family• Close relationship to proband
• High heritability of disorder
• Proband of more rarely affected sex
• Severe or early onset disease
• Multiple family members affected
All these suggest that the family has a higher liability to the disorder – genes of higher effect or more adverse
environmental influences
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial inheritance as a mode of inheritance for a condition is more likely if……
• Condition is relatively common
• Incidence in relatives lower than for single gene disorder but higher than in general population
• Risks to sibs similar to that of children
• Incidence falls rapidly in more distant relatives
• Incidence in relatives rises as the manifestations become more severe in the index case
• Risk to relatives higher when index case is of the least commonly affected sex
• Observed risk rises following the birth of two affected children
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial traits• Genetic predisposition likely to be due to a particular
combination of genes
• The genes and environmental factors causing a particular multifactorial trait may vary from person to person
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Summary
• Most diseases with a genetic component are not inherited in Mendelian fashion but display multifactorial inheritance
• Multifactorial disease usually polygenic -many genes each with small additive effects
• Major effort to identify common disease susceptibility genes underway
• Identification of SNPs associated with disease susceptibility
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
No.of individuals in population
Liability
In multifactorial disorders, the liability curve is made up of genetic and environmental factors
Low liability
Average liability
High liability
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
No.of individuals in population
Height
Continuous traits – blood pressure, height
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
No.of individuals in population
Liability
In multifactorial disorders, there is a threshold, above which a person will develop the multifactorial disorder
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
No.of individuals in population
Liability
In multifactorial disorders, there is a threshold, above which a person will develop the multifactorial disorder
Threshold
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial disorders – practice points
Common conditions“Environmental” influences act with a
genetic predispositionMultiple genes with individually small
risks often implicated One organ system affected
Recurrence risks:- “empiric figures”- obtained from population studies- use in population from
which obtained No.of affectedindividuals
Liability (genetic and environmental
factors)
Threshold
+ environment
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Risk factors for coronary artery disease
Uncontrollable (but identifiable)
Family history (genetics)AgeMale sex
Potentially controllable or treatable
Fatty dietHypertensionSmokingHigh serum cholesterolLow serum HDLHigh serum LDLStressInsufficient exerciseObesityDiabetes
Major effort to identify common disease susceptibility genes underway
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
How can the probability of recurrence be
determined for multifactorial disorders? • The recurrence risk for multifactorial disorders has to be
determined through family studies
• Observe the number of affected siblings in many families (empiric risk)
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
How evidence is gathered for genetic factors in complex diseases
• Familial risks(what is the incidence of a disorder in relatives compared with the incidence in the general population?)
• Twin studies(what is the incidence in monozygotic compared with dizygotic twins?)
• Adoption studies(what is the incidence in adopted children of the disorders which their parent had?)
• Population and Migration studies(what is the incidence in people from a particular ancestry group when they move to a different geographical area?)
Evidence from these types of studies can estimate the heritability of a condition - the proportion of the aetiology ascribed to genetic factors rather than environmental factors
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Do both twins show the same characteristic or trait?
Comparing MZ/DZ twins can give evidence for genetic and/or environmental influences
60%90%IQ
52%95%Height
DizygoticMonozygotic
Concordance rateTrait
MZ twins share all their genes and environment DZ twins share 50% genes and environment
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Determining the incidence of a disease in twins helps delineate whether there are genetic and
environmental components
11%56%Diabetes mellitus
9%19%Coronary artery disease
24%47%Asthma
7%34%Rheumatoid arthritis
8%38%Cleft lip and palate
5%67%Manic depressive psychosis
Non-identical
(DZ)
Identical (MZ)
ConcordanceDisease
Both genetic and environmental factors important
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Proband Siblings of proband
Families with one child with
multifactorial
condition
50 brothers
and sisters
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Proband Siblings of proband
50 brothers
and sisters
2 affected with
multifactorial
condition
Families with one child with
multifactorial
condition
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Proband Siblings of proband
Therefore probability of recurrence =
1/25 (4%)
2/50 affected
with multifactor
ial conditionFamilies
with one child with
multifactorial
condition
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Common diseases
• Congenital malformationsCleft lip/palateCongenital hip dislocation Congenital heart defectsNeural tube defectsPyloric stenosisTalipes
• Adult onset disorders Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia
© 2009 NHS National Genetics Education and Development Centre
Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk
Multifactorial
• Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension
• Caused by a combination of genetic predisposition and environmental influences
• Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns