Complex Genetic Traits Kate Garber Director of Education Emory University Dept. of Human Genetics email@example.com
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 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 Average Height Data from Korea Center for Disease Control and Prevention US Centers for Disease Control and Prevention
Environmental Influences on Human Height High socioeconomic status Low socioeconomic status Martorell et al.
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)
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
“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
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
% 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 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
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 • 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
General Population Affected Population Allele 1 Association with allele 1 Allele 2 Allele 3 Allele 4 Genetic Association Analysis
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? • 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 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, 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 • 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? • 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