Medical Genomics – Lecture 10 – Complex Trait Genetics
Complex diseases; diseases that not show Mendelian inheritance (example:
mutations in mitochondrial genome)
Autosomal dominant inheritance with genomic imprinting.
Complexity caused by;
• Genetic reasons (genomic imprinting)
• Genetic heterogeneity (involvement of multiple genes)
• Interaction of genes and environment
Genomic imprinting; een bepaalde allel komt tot expressie (actief is) wanneer het van
1 specifieke ouder afkomstig is.
• Maternal imprinting; allel afkomstig van moeder ingeprent en dus niet actief
• Paternal impriting; allel afkomstig van vader ingeprent en dus niet actief
Determining the genetic component of a disease
Phentoype = genetic + environment (has large power)
Quantify the genetic component;
Family aggregation studies
Familial clustering; look to frequency of disease within family
Recurrence risk (); the risk that an individual related to an affected individual will
develop the disease / the risk that someone in the population at large (random) will
develop illness.
Familial aggregation; in the family the risk for the disease among the average of the
country
Disadvantage; not determine if cause of the disease lies by the genetic or
environment
Familial recurrence risk (); risk for family members/population risk
Population studies
Compare population with similar genetics that live in different environments.
Twin studies
Genetics
DZ; disease recessive (25%), disease dominant (50%
MZ; 100%
Genes/heritability; h^2 = 2*(rMZ-rDZ)
Shared environment; C^2 = (2*rDZ)-rMZ
Unique environment; e^2 = 1-rMZ
Environment
The percentage will lie lower
Heritability (h^2); says something about the reason why individual differ from each
other. It is a ratio that is specific for the population.
, Twin studies difficult because look only to one point on the timeline.
Penetrance = probability to develop disease given risk genotype
Relative risk = probability to develop disease given risk factor (family member with
disease)
Familial Relative risk = penetrance * relative risk / population risk
Finding disease genes for complex traits
To understand complex disease compare them to monogenic diseases.
Monogenic disorder (Mendelian disorders);
• Disease phenotype determine by one gene, located in the nuclear or
mitochondrial DNA.
Mutation caused in nuclear DNA disease is referred to Mendelian.
Mitochondrial disease can be caused by mutation in nuclear disease than
referred to Mendelian or mutation in mitochondrial genome then the pattern of
inheritance will be different from what is observed in Mendelian.
• Occurring rare <0,1%
• Disease mutation are rare
Multifactorial (complex) disorders;
• Disease phenotype determined by more than one gene and environmental
factors
o Disease characterized by 2 – 4 genes = oligogenic
o Disease characterized by greater number = polygenic
• Occurring more often >0,1%
• Disease mutations are common
Before finding complex disease gene, first determine if there is a genetic component
to the disease.
Many genes are involved in a complex disease trait, one gene may predispose
(vatbaar maken) individual to illness.
• Incomplete penetrance; extra force needed from other genes before disease
occurs
• Phenocopies person; develop disease without a predisposing gene (like
mutation)
Complex disease work on different modes
1. Quantitative trait; disease become worse with the amount of
mutations
2. Threshold effects; multiple genes and environmental factors
combine to push phenotype into a discrete disease state
Bell curve/normal distribution/a Gaussian; curve for continuous traits.
The environmental factors will cause the curve to move or change shape
Alleles;
M(for Mendelian); allele is autosomal dominant
C(for complex); allele will increase person’s risk of developing disease
Complex diseases; diseases that not show Mendelian inheritance (example:
mutations in mitochondrial genome)
Autosomal dominant inheritance with genomic imprinting.
Complexity caused by;
• Genetic reasons (genomic imprinting)
• Genetic heterogeneity (involvement of multiple genes)
• Interaction of genes and environment
Genomic imprinting; een bepaalde allel komt tot expressie (actief is) wanneer het van
1 specifieke ouder afkomstig is.
• Maternal imprinting; allel afkomstig van moeder ingeprent en dus niet actief
• Paternal impriting; allel afkomstig van vader ingeprent en dus niet actief
Determining the genetic component of a disease
Phentoype = genetic + environment (has large power)
Quantify the genetic component;
Family aggregation studies
Familial clustering; look to frequency of disease within family
Recurrence risk (); the risk that an individual related to an affected individual will
develop the disease / the risk that someone in the population at large (random) will
develop illness.
Familial aggregation; in the family the risk for the disease among the average of the
country
Disadvantage; not determine if cause of the disease lies by the genetic or
environment
Familial recurrence risk (); risk for family members/population risk
Population studies
Compare population with similar genetics that live in different environments.
Twin studies
Genetics
DZ; disease recessive (25%), disease dominant (50%
MZ; 100%
Genes/heritability; h^2 = 2*(rMZ-rDZ)
Shared environment; C^2 = (2*rDZ)-rMZ
Unique environment; e^2 = 1-rMZ
Environment
The percentage will lie lower
Heritability (h^2); says something about the reason why individual differ from each
other. It is a ratio that is specific for the population.
, Twin studies difficult because look only to one point on the timeline.
Penetrance = probability to develop disease given risk genotype
Relative risk = probability to develop disease given risk factor (family member with
disease)
Familial Relative risk = penetrance * relative risk / population risk
Finding disease genes for complex traits
To understand complex disease compare them to monogenic diseases.
Monogenic disorder (Mendelian disorders);
• Disease phenotype determine by one gene, located in the nuclear or
mitochondrial DNA.
Mutation caused in nuclear DNA disease is referred to Mendelian.
Mitochondrial disease can be caused by mutation in nuclear disease than
referred to Mendelian or mutation in mitochondrial genome then the pattern of
inheritance will be different from what is observed in Mendelian.
• Occurring rare <0,1%
• Disease mutation are rare
Multifactorial (complex) disorders;
• Disease phenotype determined by more than one gene and environmental
factors
o Disease characterized by 2 – 4 genes = oligogenic
o Disease characterized by greater number = polygenic
• Occurring more often >0,1%
• Disease mutations are common
Before finding complex disease gene, first determine if there is a genetic component
to the disease.
Many genes are involved in a complex disease trait, one gene may predispose
(vatbaar maken) individual to illness.
• Incomplete penetrance; extra force needed from other genes before disease
occurs
• Phenocopies person; develop disease without a predisposing gene (like
mutation)
Complex disease work on different modes
1. Quantitative trait; disease become worse with the amount of
mutations
2. Threshold effects; multiple genes and environmental factors
combine to push phenotype into a discrete disease state
Bell curve/normal distribution/a Gaussian; curve for continuous traits.
The environmental factors will cause the curve to move or change shape
Alleles;
M(for Mendelian); allele is autosomal dominant
C(for complex); allele will increase person’s risk of developing disease
