From Iusmgenetics

Contents 1 Genetic Mapping of Complex Disease 1.1 Complex Disease 1.2 Is it Genetic? 1.2.1 Twin Studies 1.2.2 Familial Aggregation 1.2.3 Mendelian forms of disease 1.2.4 Animal models 1.3 Genetics of Complex Disease 1.3.1 Multifactorial Liability Threshold Model 1.4 Risk Factor Concepts 1.4.1 Risk factor 1: Sex differences 1.4.2 Risk Factor 2: Degree of Relationship 1.4.3 Risk factor 3: severity of the defect 1.4.4 Risk Factor 4: Number of Affected Individuals 1.5 Incidence vs. Prevalence 1.6 Counseling in Multifactorial Traits 1.7 New types of genetic data 1.7.1 (Genetically) Personalized Medicine 1.7.2 “Missing heritability”

Genetic Mapping of Complex Disease

Complex Disease

• Both genes and environmental factors contribute to disease risk
• Genetic diseases seen most often in clinical practice
• Few genes and few environmental factors have been identified for these conditions
• Active area of research

• Examples of Complex Disease:
  • Atherosclerosis
  • Multiple Sclerosis
  • Diabetes mellitus
  • Alzheimer Disease
  • Epilepsy
  • Alcoholism
  • Dementia
  • Oral Clefts
  • Schizophrenia
  • Inflammatory Bowel Disease
  • Neural Tube Defects
  • Skeletal Disorders
  • Hypertension
  • Lung Cancer
  • Obesity
  • Parkinson Disease
  • Breast Cancer
  • Bipolar (manic depressive)
  • Depression

Is it Genetic?

• Single gene (Mendelian) disorders
  • obvious they are genetic
  • reviewing pedigrees makes the mode of inheritance obvious
    • Autosomal recessive (Phenylketonuria)
    • Autosomal dominant (Huntington Disease)
    • X-linked recessive (Duchenne muscular dystrophy)

• Other disorders, it appears that genetics is important
• But, there is NO recognizable pattern of inheritance

• How to prove a disease has a genetic component?
  • Twin Studies
  • Familial Aggregation
  • Mendelian Form of Disease
  • Animal Models

Twin Studies

• Compare Monozygotic and Dizygotic Twins
  • Monozygotic Twins: genetically identical
  • Dizygotic Twins: like siblings (1/2 genome shared)
• Compare concordance rates of MZ and DZ twins

Familial Aggregation

• Increased risk for disease among family members of an affected individual
• Compare frequency of disease among first degree relatives of affected individuals with the frequency of the disease in the general population.

Mendelian forms of disease

• Breast Cancer
  • BRCA1, BRCA2
• Alzheimer Disease
  • Amyloid precursor protein, presenilin 1 and 2
• Parkinson Disease
  • alpha synuclein
  • parkin (autosomal recessive)

Animal models

• Identification of inbred animal strains with consistent findings of disease characteristics can be a useful predictor that a trait is genetic.
  • Can then perform experiments with controlled environment and planned mating to identify genes
• Hypertension
  • Rat lines that are stroke resistant and stroke prone

Genetics of Complex Disease

• Polygenic: determined by multiple genes
• Multifactorial: determined by both genes and environmental factors

Multifactorial Liability Threshold Model

• Theoretical model designed to provide a means to explain gene interactions as well as possible environmental interaction with disease susceptibility
• Has not been proven to be true, but predictions of model are consistent with observations from clinical patients and their families

• Hypothesize that only those individuals who have inherited a sufficient number of susceptibility alleles at various genes will develop disease.
• Postulate that milder forms of the disease might be due to smaller number of susceptibility alleles.

Risk Factor Concepts

• There are four types of risk factors: sex, degree of relationship (to relation with disease state), severity of defect, number of individuals in pedigree

Risk factor 1: Sex differences

• Some disorders have differing frequencies among the genders
  • individuals of the more rarely affected sex would need more susceptibility alleles to manifest disease
  • individuals of the more commonly affected sex would need fewer susceptibility alleles to manifest disease

• For example:
  • This model females are less often affected
  • Consider relatives of an affected male, the liability is shifted to the right, therefore increased risk of both affected male and female relatives
  • Consider relatives of an affected female, the liability is shifted even further to the right, therefore even more increased risk of both affected males and female relatives

Risk Factor 2: Degree of Relationship

• First Degree: Share 1/2 of genes
  • parents, children, siblings
• Second Degree: Share 1/4 of genes
  • uncles / aunts, nieces / nephews, g’parent, g’child, half-siblings
• Third Degree: Share 1/8 of genes
  • 1st cousins, g-g’parent, g-g’child, half-uncle / aunts, half-nephew / nieces

• Risk drops for 2nd degree relatives
  • It is expected that more closely related individuals would share more alleles in common than more distantly related relatives
  • Individuals more closely related to an affected individual are at higher risk of also being affected

Risk factor 3: severity of the defect

• Recurrence risk increases if the trait is more severe
  • More severe phenotype requires more susceptibility alleles
  • Greater risk for any spectrum of the phenotype (mild to severe)

• Cleft Lip and Palate:
  • 60-80% of affected are male
  • Different causes:
    • isolated single gene (Mendelian inheritance)
    • part of a syndrome
    • teratogen
    • several genes/environment (Multifactorial)
  • Racial differences

• Different thresholds for different levels of disease severity
  • Consider relatives of a less severely affected individual, the liability is shifted to the right, therefore increased risk of both males and female relatives to be affected with any form of disease (mild to severe).
  • Consider relatives of a more severely affected individual, the liability is shifted even further to the right, therefore even more increased risk of both males and female relatives to be affected with any form of disease (mild to severe)

Risk Factor 4: Number of Affected Individuals

• If there is more than 1 affected individual in the pedigree:
  • recurrence risk increases
  • suggests that the family might have even more susceptibility alleles segregating
• Be sure to also consider whether the family might have a single gene disorder
  • any other dysmorphism suggesting a syndrome?

Incidence vs. Prevalence

• Incidence: Proportion of individuals who have a disorder at birth.
• Prevalence: Number of individuals with a disorder in a given population at a particular time.

Counseling in Multifactorial Traits

• Recurrence risk for 1st degree relatives of an affected individual is square root of population incidence
• Example: Ventricular septal defect:
  • population incidence = 1/575
  • square root of 575 = ~24
  • recurrence risk for 1st degree relatives = 1/24
  • convert percentages to decimals or fractions!

New types of genetic data

• Genome-wide SNP markers:
  • ~1 million SNPs to tag all common variants in an individual’s genome (~400 USD)
• Sequence data (whole-exome or -genome)
  • Identify all 60,000-100,000 rare and common variants in an individual’s genome
  • Rapidly becoming feasible (“$1,000 genome”)
  • Sequencing error rates low with current technology, but large numbers of false variants remain in any one person’s sequence

(Genetically) Personalized Medicine

• Challenge is interpretation
• We expect to identify both:
  • Rare variants that explain disease in a particular person / family
  • Variants that increase susceptibility to disease across an ethnic group or larger population
• How to translate this to prognosis, lifestyle modification recommendations, etc. in any one individual??

“Missing heritability”

• GWAS studies typically detect common variants explaining <20% (combined) of total variation
• What could explain the difference?
  • Gene-gene interactions (epistasis)
  • Gene-environment interactions
• Only a very small proportion of variation in trait or disease risk is explained by combined effects of common SNPs.