Complex genetic traits
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Complex Genetic Traits. Kate Garber Director of Education Emory University Dept. of Human Genetics [email protected] Objectives. Understand the concept of threshold liability and the complex interplay of genes and environment in determining many heritable traits

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Complex Genetic Traits

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Complex genetic traits

Complex Genetic Traits

Kate Garber

Director of Education

Emory University Dept. of Human Genetics

[email protected]


Objectives

Objectives

  • Understand the concept of threshold liability and the complex interplay of genes and environment in determining many heritable traits

  • State the key advances that facilitated the recent explosion in genes being identified for complex traits

  • Understand what these genetic associations with complex traits mean for medicine


Complex genetic traits

Mendelian versus complex traits

  • Mendelian traits

    • Are determined by the independent action of a single major gene

    • Mutation in this gene is necessary and sufficient for phenotype

    • Have predictable inheritance patterns

Cystic fibrosis

Risk to each sib is 25% and we can do prenatal testing


Mendelian versus complex traits

Mendelian versus complex traits

  • Complex traits

    • Are determined by interactions between multiple genetic and environmental risk factors

    • Exhibit familial clustering but not predictable inheritance patterns

Cleft palate

Recurrence risk is 3% (compared to population risk of 0.1%)


Mendelian versus complex traits1

Mendelian versus Complex Traits

Complex Traits

Genetic variation that contributes to a complex

genetic disease usually results in

a change to the level of the encoded protein

or the level of protein activity.

Simple Traits

Genetic variation that causes Mendelian

genetic disease usually results in

a loss of the encoded protein or a change

in the protein’s activity.


Human height

Human height


Genetic environmental influences on height

Genetic Environmental Influences on Height

Average Height

Data from Korea Center for Disease Control and Prevention

US Centers for Disease Control and Prevention


Environmental influences on human height

Environmental Influences on Human Height

High socioeconomic status

Low socioeconomic status

Martorell et al.


Complex diseases have a genetic and environmental component

gene 3

environment

environment

gene 1

gene 2

environment

“Complex” diseases have a genetic and environmental component

Examples:

•Asthma

•Diabetes

•Hypertension

•Coronary Artery Disease

•Alzheimer Disease

•Schizophrenia

•Depression

Physical trait

(disease)


Complex disorders the environment genetic scale

genetic

environmental

Complex Disorders: the environment/genetic scale

Common

Complex genetics

Low recurrence risk

Rare

Simple genetics

High recurrence risk

Sickle cell disease

Hypertension

Heart disease

Diabetes

Asthma

Behavioral disorders

Scurvy;

Infectious diseases


Gene environment interaction in cardiac disease

“Some vegetarians with 'acceptable' cholesterol levels suffer myocardial infarction in the 30's. Other individuals...seem to live forever despite personal stress, smoking, obesity, and poor adherence to a Heart Association-approved diet"

Gene-Environment Interaction in Cardiac Disease

R.A. Hegele (1992) The Canadian Medical Association Journal


Family history

Family History


Family history as a warning sign

Darryl Kile of the St. Louis Cardinals died in 2002 at the age of 33

“Kile's father's death from cardiovascular disease in his 40s should have been a red flag signaling that the pitcher had an increased risk of the same fate”

Family History as a Warning Sign


Contributions to a complex trait

% risk to individual 2

major gene a

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

minor gene a

minor gene b

minor gene c

exposure a

exposure b

Contributions to a complex trait

% risk to individual 1


Threshold model of liability

Threshold Model of Liability

Assumes there is a liability towards development of a specific disorder – liability is normally distributed among the population

Liability is comprised of both genetic and environmental influences

threshold

When the threshold of liability is crossed, the trait appears

# individuals

affected

Liability


Complex genetic traits

New York Times 7/19/2007

Scientists Find Genetic Link for (Restless Leg) Disorder

Boston Globe January 16, 2006

Research links gene to Type 2 diabetes

CBS News April 12, 2007

Study Finds First Genetic Link For Obesity

Common Variation In FTO Gene May Make Obesity More Likely

Science Daily July 12, 2007

Gallstone Gene Discovered: Gene Variant Causes Two- To

Three-fold Increase In Risk


Genetic markers

Genetic markers

  • Known variable genetic loci that can be genotyped by a simple assay.

  • They do not have to be located within a gene (and often are not)

  • A SNP is one type of genetic marker but there are others

  • It is believed that there is likely to be common genetic variation that underlies common traits


Genetic association analysis

General Population

Affected Population

Allele 1

Association with allele 1

Allele 2

Allele 3

Allele 4

Genetic Association Analysis


False positive associations

False Positive Associations

Results:

Chopstick use is determined by

the HLA locus (used in organ

donor matching)

  • Recruit study sample in San Francisco

  • Divide sample based on ability to use chopsticks

  • Perform genetic association study

Why?

HLA alleles are distributed

differently in Asians, Caucasians,

Africans, and there are more

Asians in the “case” sample. The

result is due to a cultural

association, not genetics.


What markers do you test

What markers do you test?

  • Candidate gene analysis

  • Based on prior localization information from affected families

  • Genome-wide scan


Advances that have made whole genome association studies possible

Advances that have made Whole Genome Association Studies possible

  • Improved methods for whole genome amplification

  • Advances in statistical methodology

  • Array technologies

    • Simultaneous genotyping of 0.5-1 million SNPs

  • The International HapMap


Hapmap

HapMap

  • Catalog of common human genetic variation across the genome

    • “Common” was taken to mean that the more rare allele was in at least 5% of the population

  • 1 Million SNPs were genotyped in 269 samples comprising 4 populations

  • Associations between SNPs have been identified and catalogued


Marker selection

Marker Selection

From Christensen and Murray (2007) NEJM 356:1094-1097


Marker selection for whole genome studies

Marker Selection for Whole Genome Studies

  • Using information from the HapMap, it is possible to select a set of ~300,000-600,000 SNPs that will represent all variation in the genome

  • Using array technologies, it is possible to genotype this many SNPs at once

  • Based on Common Disease-Common Variant Hypothesis


Genetic associations for complex diseases

Genetic Associations for Complex Diseases

  • CFH gene and macular degeneration

    • The SNP changes the protein sequence

  • TCF7L2 and Type 2 Diabetes

    • No mutations in exons. Variation associated with changes in the level of gene expression

  • Marker on chromosome 9 and Coronary Artery Disease

    • No mutations in neighboring genes


Apoe and alzheimer disease

APOE and Alzheimer Disease

  • Alzheimer Disease is a heritable trait

  • One of the genetic determinants of AD is APOE

  • People homozygous for APOE 4 are at 20-fold increased risk of AD compared to people who don’t carry the allele

  • Should we do genetic testing of APOE?


Apoe and alzheimer disease1

APOE and Alzheimer Disease

  • 1.5% of the population is homozygous for APOE 4

  • < 1/4 of these people will get the disease

  • There’s no intervention

  • Genetic testing is not done in presymptomatic individuals

However, genetic testing for APOE is done in some situations -when?

In individuals with dementia, to support diagnosis of AD


Boston globe january 16 2006 research links gene to type 2 diabetes

Boston Globe January 16, 2006Research links gene to Type 2 diabetes

A particular allele in the TCF7L2 gene was more common in people with Type 2 Diabetes than a set of controls


Tcf7l2 and type 2 diabetes

TCF7L2 and Type 2 Diabetes


Genetic testing for type 2 diabetes

Genetic Testing for Type 2 Diabetes

  • Should we allow this testing?

    • Motivation to change environmental risk factors?

  • If so, should we allow individuals to order the testing themselves?

  • Potential use of test in selection of diabetes prevention strategy


Complex genetic traits

Homozygous for TCF7L2 risk allele

Flores et al. (2006) NEJM 355:241-250


Why do these association studies

Why do these association studies?

  • Can identify biological pathways involved in disease

    • Helps us understand the disease process

    • May provide therapeutic targets

  • May ultimately help with choice of therapy

    • Pharmacogenetics


Complex genetic traits

  • Marker on chromosome 9 and Coronary Artery Disease

    • No mutations in neighboring genes

  • What do we do with this information?


Genome content the traditional view

Genome Content: The Traditional View

~1.5% of the genome is composed of protein-coding genes

  • Humans have around 21,000 genes.

4% of the genome are regulatory elements of genes: these serve to enhance/suppress the activity of genes

The other 95% is junk.


The encode project

The ENCODE project

  • ENCyclopedia Of DNA Elements

    Some of the key findings so far:

  • Almost all bases in the genome are transcribed into RNA

  • Regulatory elements are symmetrically located (not just upstream of genes)


Some of the junk repetitive dna

Some of the “junk”: Repetitive DNA

  • Minisatellite

    • 10-100 basepair core sequence

    • Generates VNTR (Variable number of tandem repeat) polymorphisms


Repetitive dna

Repetitive DNA

  • Microsatellite

    • 2-4 nucleotides

    • aka Short tandem repeats (STRs)

    • A standard set of 13 of these markers is used by the CODIS criminal DNA database for identity testing (DNA fingerprinting)


Looking at repetitive dna

Looking at repetitive DNA

Person 1

Person 2


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