1. Genetics 101 Complex Genetic Traits Kate Garber Director of Education Emory University Dept. of Human Genetics kgarber@genetics.emory.edu

2. Genetics 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

3. Genetics 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

4. Genetics 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%)

5. Genetics 101 Mendelian versus Complex Traits Simple Traits Genetic variation that causes Mendelian genetic disease usually results in a loss of the encoded protein or a change in the proteins activity. 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.

6. Genetics 101 Human height

7. Genetics 101 Genetic Environmental Influences on Height United StatesSouth KoreaNorth Korea Males5 9.55 8.55 4.5 Females5 45 3.55 1.0 Data from Korea Center for Disease Control and Prevention US Centers for Disease Control and Prevention Average Height

8. Genetics 101 Environmental Influences on Human Height High socioeconomic status Low socioeconomic status Martorell et al.

9. Genetics 101 Complex diseases have a genetic and environmental component Physical trait (disease) gene 1 gene 2 gene 3 environment Examples: Asthma Diabetes Hypertension Coronary Artery Disease Alzheimer Disease Schizophrenia Depression

10. Genetics 101 Complex Disorders: the environment/genetic scale environmentalgeneticRare Simple genetics High recurrence risk Common Complex genetics Low recurrence risk Sickle cell disease Scurvy; Infectious diseases Hypertension Heart disease DiabetesAsthma Behavioral disorders

11. Genetics 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 Journal

12. Genetics 101 Family History

13. Genetics 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

14. Genetics 101 Contributions to a complex trait minor gene a minor gene c exposure b exposure a major gene a minor gene b 100 90 80 70 60 50 40 30 20 10 0 % risk to individual 1 100 90 80 70 60 50 40 30 20 10 0 % risk to individual 2

15. Genetics 101 Threshold Model of Liability Liability # individuals threshold affected 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

16. Genetics 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 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

17. Genetics 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

18. Genetics 101 Genetic Association Analysis Allele 1 Allele 2 Allele 3 Allele 4 General PopulationAffected Population Association with allele 1

19. Genetics 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 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.

20. Genetics 101 What markers do you test? Candidate gene analysis Based on prior localization information from affected families Genome-wide scan

21. Genetics 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

22. Genetics 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

23. Genetics 101 Marker Selection From Christensen and Murray (2007) NEJM 356:1094-1097

24. Genetics 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

25. Genetics 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

26. Genetics 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 dont carry the allele Should we do genetic testing of APOE?

27. Genetics 101 APOE and Alzheimer Disease 1.5% of the population is homozygous for APOE 4 < 1/4 of these people will get the disease Theres 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

28. Genetics 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

29. Genetics 101 TCF7L2 and Type 2 Diabetes

30. Genetics 101

32. 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

33. Genetics 101 Flores et al. (2006) NEJM 355:241-250 Homozygous for TCF7L2 risk allele

34. Genetics 101

35. 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

36. Genetics 101 Marker on chromosome 9 and Coronary Artery Disease – No mutations in neighboring genes What do we do with this information?

37. Genetics 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.

38. Genetics 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)

39. Genetics 101 Some of the junk: Repetitive DNA Minisatellite –10-100 basepair core sequence –Generates VNTR (Variable number of tandem repeat) polymorphisms

40. Genetics 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)

41. Genetics 101 Looking at repetitive DNA Person 1 Person 2

42. Genetics 101