Genetics 101 Complex Genetic Traits Kate Garber Director of Education Emory University Dept. of...

Genetics 101Genetics 101

Complex Genetic Traits

Kate GarberDirector 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

• 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• 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 Traits

Simple TraitsGenetic variation that causes Mendeliangenetic disease usually results in a loss of the encoded protein or a change in the protein’s activity.

Complex TraitsGenetic variation that contributes to a complexgenetic disease usually results in a change to the level of the encoded proteinor the level of protein activity.


Human height


Genetic Environmental Influences on Height

United States

South Korea

North Korea

Males 5’ 9.5” 5’ 8.5” 5’ 4.5”

Females 5’ 4” 5’ 3.5” 5’ 1.0”

Data from Korea Center for Disease Control and Prevention US Centers for Disease Control and Prevention

Average Height


Environmental Influences on Human Height

High socioeconomic status

Low socioeconomic status

Martorell et al.


“Complex” diseases have a genetic and environmental component

Physical trait(disease)

gene 1 gene 2

gene 3

environment

environmentenvironment

Examples:

• Asthma

• Diabetes

• Hypertension

• Coronary Artery Disease

• Alzheimer Disease

• Schizophrenia

• Depression

Genetics 101Genetics 101Complex Disorders: the Complex Disorders: the environment/genetic scale environment/genetic scale

environmentalenvironmentalgeneticgenetic

RareRareSimple geneticsSimple genetics

High recurrence riskHigh recurrence risk

CommonCommonComplex geneticsComplex geneticsLow recurrence riskLow recurrence risk

Sickle cell Sickle cell diseasedisease

Scurvy;Scurvy;Infectious Infectious diseasesdiseases

HypertensionHypertensionHeart diseaseHeart disease

DiabetesDiabetesAsthmaAsthma

Behavioral disordersBehavioral disorders


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"

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


Family History


• 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 traitContributions to a complex trait

minor gene a

minor gene c

exposure b

exposure a

major gene a

minor gene b

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% risk to individual 1

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% risk to individual 2


Threshold Model of LiabilityThreshold Model of Liability

LiabilityLiability

# in

divi

du

als

# in

divi

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thresholdthreshold

affectedaffected

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

Liability is comprised of both genetic and environmental Liability is comprised of both genetic and environmental influencesinfluences

When the threshold When the threshold of liability is of liability is crossed, the trait crossed, the trait appearsappears


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 ObesityCommon 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

• 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 AnalysisGenetic Association Analysis

Allele 1

Allele 2

Allele 3

Allele 4

General Population Affected Population

Association with allele 1Association with allele 1


False Positive Associations

• Recruit study sample in San Francisco

• Divide sample based on ability to use chopsticks

• Perform genetic association study

Results:Chopstick use is determined by the HLA locus (used in organ donor matching)

Why?HLA alleles are distributeddifferently 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?

• Candidate gene analysis• Based on prior localization information from

affected families• Genome-wide scan


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• 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

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


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• 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

• 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 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

individualsHowever, 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

• 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

Risk of Type 2 Diabetes

0

20

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Lifetime OX XX

Ris

k (%

)


0

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OO OX XX

Fraction that Won't Get 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


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

Homozygous for TCF7L2 risk allele


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

~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

• 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

• Minisatellite– 10-100 basepair

core sequence – Generates VNTR

(Variable number of tandem repeat) polymorphisms


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

Person 1

Person 2

Genetics 101 Complex Genetic Traits Kate Garber Director of Education Emory University Dept. of...

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