Genetics of common complex disease and single-nucleotide polymorphism (SNP)

Complex disease

Disease caused by the combined effects of multiple genes and environmental factors

Polygenic disease

Disease influenced by many genes each contributing a small effect

Multifactorial disease

Disease resulting from both genetic and environmental influences

Single-gene disorder

Disease caused by mutation in one gene with a large effect

Mendelian inheritance

Predictable inheritance pattern following dominant, recessive, X-linked or Y-linked transmission

Autosomal dominant

One mutant allele is sufficient to cause disease

Autosomal recessive

Two mutant alleles are required to cause disease

X-linked disorder

Disorder caused by mutations on the X chromosome

Y-linked disorder

Disorder caused by mutations on the Y chromosome

Major difference between single-gene and complex diseases

Single-gene diseases are caused by one major mutation whereas complex diseases involve many genes and environmental factors

Frequency of single-gene disorders

Generally rare in the population

Frequency of polygenic disorders

Generally common in the population

Effect size in single-gene disorders

Large effect from one gene mutation

Effect size in polygenic disorders

Small contribution from many genes

Environmental influence in complex disease

Often a major determinant of disease risk and progression

Inheritance pattern in complex disease

No clear Mendelian inheritance pattern

Example of a single-gene disorder

Cystic fibrosis

Example of a complex disease

Type 2 diabetes mellitus

Genetic characteristic of complex diseases

Multiple susceptibility genes contribute to disease risk

Why are polygenic diseases common?

Risk alleles have small effects and may persist due to selective advantages or late onset of disease

Homeostasis in complex disease

Gradually disturbed by accumulation of genetic and environmental risk factors

Gradual disturbance of homeostasis

Progressive movement toward disease rather than sudden onset from one mutation

Polygenic trait

Trait influenced by multiple genes

Continuous trait

Trait showing a range of values with a normal distribution

Examples of continuous traits

Height, weight and blood pressure

Discontinuous trait

Trait expressed as affected or unaffected

Examples of discontinuous traits

Type 1 diabetes and cleft lip

Quantitative trait

Another term for continuous trait

Qualitative trait

Another term for discontinuous trait

Why do continuous traits show a normal distribution?

Many genes contribute additively to the phenotype

Additive genetic effect

Each gene contributes a small amount to the final trait value

Threshold model of susceptibility

Disease occurs only when liability exceeds a critical threshold

Liability

Overall genetic and environmental susceptibility to disease

Components of liability

Genetic factors plus environmental factors

Threshold

Point at which disease manifests

Crossing the threshold

Accumulating sufficient genetic and environmental risk to develop disease

Individuals below the threshold

Unaffected

Individuals above the threshold

Affected

Average liability in affected families

Higher than in the general population

Why do siblings of affected individuals have higher risk?

They share more susceptibility genes and environmental exposures

Recurrence risk

Probability that a disease will occur again in a family

Factors increasing recurrence risk

More affected relatives and greater disease severity

Prediction 1 of multifactorial threshold model

Recurrence risks vary among families

Prediction 2 of multifactorial threshold model

Risk increases with the number of affected relatives

Prediction 3 of multifactorial threshold model

Risk increases with severity of disease

Prediction 4 of multifactorial threshold model

Relative risk increases as disease prevalence decreases

Prediction 5 of multifactorial threshold model

Offspring of the less commonly affected sex have higher risk

Twin study

Method used to assess genetic contribution to disease

Concordance

Probability that both individuals in a pair exhibit the same trait

Monozygotic twins

Twins derived from a single fertilized egg and genetically identical

Dizygotic twins

Twins derived from two fertilized eggs and share about 50% of genes

Interpretation of MZ concordance greater than DZ concordance

Evidence for a genetic contribution to disease

Interpretation of MZ concordance less than 100%

Environmental factors also contribute to disease

Heritability

Proportion of trait variation attributable to genetic factors

High heritability

Strong genetic influence but not necessarily complete genetic determination

Heritability of schizophrenia

Approximately 85%

Heritability of asthma

Approximately 80%

Heritability of ankylosing spondylitis

Approximately 70%

Heritability of hypertension

Approximately 62%

Heritability of osteoarthritis

Approximately 55%

Heritability of type 2 diabetes

Approximately 26%

Limitation of twin studies

MZ twins often share more similar environments than DZ twins

Bias in twin studies

MZ twins may be treated more similarly than DZ twins

Why study twins separated at birth?

To better distinguish genetic effects from environmental effects

Type 2 diabetes mellitus

Polygenic disorder characterized by insulin resistance and hyperglycaemia

Major environmental risk factors for type 2 diabetes

Obesity, high-calorie diet and physical inactivity

Insulin resistance

Reduced cellular response to insulin despite its presence

Thrifty gene hypothesis

Genes that promoted survival during famine may predispose to obesity and diabetes today

Metabolically thrifty genes

Genes that favor efficient energy storage and fat deposition

Advantage of thrifty genes in ancient environments

Improved survival during famine

Disadvantage of thrifty genes in modern environments

Increased risk of obesity and type 2 diabetes

Genetic variation

Differences in DNA sequence among individuals

Percentage of DNA shared among humans

Approximately 99.9%

Percentage of DNA contributing to individual variation

Approximately 0.1%

Single nucleotide polymorphism (SNP)

Single base pair variation present in more than 1% of the population

Mutation

Single base pair variation present in less than 1% of the population

Difference between SNP and mutation

SNPs are common whereas mutations are rare

Pronunciation of SNP

Snip

Location of SNPs

Found in both coding and noncoding regions of DNA

Most SNPs occur in

Noncoding regions

Frequency of SNPs in the genome

Approximately one every 100–1000 base pairs

Coding region SNP

May alter amino acid sequence and protein structure

Noncoding SNP

May affect gene regulation or serve as a genetic marker

Significance of SNPs

Modify disease susceptibility and contribute to phenotypic variation

Disease risk SNP

Genetic variant that increases or decreases likelihood of disease

Harmless SNP

Variation with no significant biological effect

Harmful SNP

Variation associated with disease development

Latent SNP

Variation that becomes important only under certain conditions

Why are SNPs useful in genetics?

They are abundant and easy to measure

SNP marker

A SNP located near a gene and used to track inheritance of that gene

SNP profile

Unique pattern of SNPs within an individual’s genome

Importance of SNP profiles

Can predict disease risk and drug responses

Pharmacogenomics

Study of how genetic variation influences drug response

Role of SNPs in pharmacogenomics

Help predict efficacy and toxicity of medications

Genome-wide association study (GWAS)

Method that identifies SNPs associated with disease risk

Most SNPs directly cause disease

False, most only modify susceptibility

Common diseases associated with SNPs

Diabetes, cancer and cardiovascular disease

Exam clue for genetic contribution

MZ concordance significantly exceeds DZ concordance

Exam clue for environmental contribution

MZ concordance is less than 100%

Affected individual with unaffected parents in complex disease

Common finding due to multifactorial inheritance