Genetics 101 Complex Genetic Traits Kate Garber Director of Education Emory University Dept. of Human Genetics [email protected]
Mar 31, 2015
Genetics 101Genetics 101
Complex Genetic Traits
Kate GarberDirector of Education
Emory University Dept. of Human Genetics
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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%)
Genetics 101Genetics 101
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.
Genetics 101Genetics 101
Human height
Genetics 101Genetics 101
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
Genetics 101Genetics 101
Environmental Influences on Human Height
High socioeconomic status
Low socioeconomic status
Martorell et al.
Genetics 101Genetics 101
“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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
Family History
Genetics 101Genetics 101
• 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
Genetics 101Genetics 101
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
100
90
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% risk to individual 1
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% risk to individual 2
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
Genetic Association AnalysisGenetic Association Analysis
Allele 1
Allele 2
Allele 3
Allele 4
General Population Affected Population
Association with allele 1Association with allele 1
Genetics 101Genetics 101
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.
Genetics 101Genetics 101
What markers do you test?
• Candidate gene analysis• Based on prior localization information from
affected families• Genome-wide scan
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
Marker Selection
From Christensen and Murray (2007) NEJM 356:1094-1097
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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?
Genetics 101Genetics 101
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
Genetics 101Genetics 101
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
Genetics 101Genetics 101
TCF7L2 and Type 2 Diabetes
Risk of Type 2 Diabetes
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Lifetime OX XX
Ris
k (%
)
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OO OX XX
Fraction that Won't Get Diabetes
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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
Genetics 101Genetics 101
Flores et al. (2006) NEJM 355:241-250
Homozygous for TCF7L2 risk allele
Genetics 101Genetics 101
Genetics 101Genetics 101
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
Genetics 101Genetics 101
• Marker on chromosome 9 and Coronary Artery Disease– No mutations in neighboring genes
• What do we do with this information?
Genetics 101Genetics 101
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.
Genetics 101Genetics 101
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)
Genetics 101Genetics 101
Some of the “junk”: Repetitive DNA
• Minisatellite– 10-100 basepair
core sequence – Generates VNTR
(Variable number of tandem repeat) polymorphisms
Genetics 101Genetics 101
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)
Genetics 101Genetics 101
Looking at repetitive DNA
Person 1
Person 2
Genetics 101Genetics 101