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Complex Genetic Traits. Kate Garber Director of Education Emory University Dept. of Human Genetics 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

Complex Genetic Traits

Kate Garber

Director of Education

Emory University Dept. of Human Genetics

  • 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

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.

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



gene 1

gene 2


“Complex” diseases have a genetic and environmental component


• Asthma

• Diabetes

• Hypertension

• Coronary Artery Disease

• Alzheimer Disease

• Schizophrenia

• Depression

Physical trait


complex disorders the environment genetic scale



Complex Disorders: the environment/genetic scale


Complex genetics

Low recurrence risk


Simple genetics

High recurrence risk

Sickle cell disease


Heart disease



Behavioral disorders


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 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























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


When the threshold of liability is crossed, the trait appears

# individuals




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


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


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
  • 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

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

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
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)