Genetic Epidemiology: The Interface between Science and Public Policy

1. Genetic Epidemiology: The Interface between Science and Public Policy Kathleen Ries Merikangas, Ph.D. Chief, Section on Developmental Genetic Epidemiology, Intramural Research Program National Institute of Mental Health

2. Epidemiology

3. Epidemiology is more than counting

4. The Epidemiologic Triangle Age, Sex, Race, Religion, Customs, Occupation, Genetic profile, Marital status, Family background, Prior diseases, Immune status Host Environment Agent Biologic (bacteria, viruses), Chemical (poison, alcohol, smoke), Physical (trauma, radiation, fire), Nutritional (lack, excess) Temperature, Humidity, Altitude, Crowding, Housing, Neighborhood, Water, Milk, Food, Radiation, Noise, Air pollution

5. Taubes, G., Science, 169:164-169, 1995

6. Family history is an independent risk factor for most chronic diseases of public health significance

7. Genetics

9. Mendelian Disorders • The gene loci are now known for nearly all of the Mendelian Disorders • N of Mendelian disorders: • 40 cancer syndromes • 50 cardiovascular diseases • 29 diabetes subtypes Scheuner et al, 2004

11. Complex Disorders

12. Status of Gene Identification for Complex Diseases • Identification of genes for complex diseases has not been highly successful to date • Most disease genes that have been identified are rare with high absolute risk but low population attributable risk

13. Complex patterns of disease transmission • Non-Mendelian patterns of transmission: • Phenotypic and genotypic heterogeneity • Polygenic or oligogenic inheritance • Gene-environment interaction • Epistasis (gene-gene interaction) • Variable expressivity • Penetrance

14. Genetic Epidemiology

15. Goals: Genetic Epidemiology • to examine the distribution, risk factors & the inherited causes of disease, either through genes or culture, in groups of relatives • to identify the etiology of a disease and thereby prevent or intervene in the progression of the disorder

16. Application of Genetic Epidemiologic Study Designs • to identify the mode of transmission • to identify most heritable phenotypes • to detect gene - environment interaction • to establish population base rates of disease and genetic markers

17. Summary: Risk Ratios for Complex Disorders Risk Ratios Disorder 1 relative > 2 relatives Asthma 2.3 3.9 Alzheimer’s (< 50) 2.8 4.3 Cancer Breast 2.1 3.9 Colorectal 1.7 4.9 Prostate 3.2 11.0 Cardiovascular 2.0 3.4 Diabetes II 2.4 ----- Yoon et al, 2002

18. The decrement in concordance rates between MZ and DZ twins is significantly different from 50% for most mental disorders Disorder MZ DZ Autism .60 .05 Bipolar Disorder .63 .12 Schizophrenia .58 .08 Substance Abuse .60 .40 Tourette Syndrome .53 .08

19. BRCA Mutations & Breast Cancer Family Group N BRCA1 BRCA2 Other No Males 211 .55 .26 .19 Male Breast 26 .16 .76 .08 Breast/Ovarian 94 .81 .14 .05 Female Breast 117 .26 .32 .42 All Families 223 .52 .32 .16 Ford et al, 1998

20. Association between Nicotine Use in Probands and Relatives Adjusted Odds Ratios Parents Siblings Offspring Spouse Proband n=74 n=131 n=56 n=123 Regular Use 0.9 1.2 0.7 1.6 Dependence 0.8 2.7 0.7 2.4

21. How do we know that environmental factors are involved in a disease? • > 50% decrement in the recurrence risk in families by degree of genetic relationship • Increased prevalence of disease among non-biological relatives (eg., spouses) • Change in disease prevalence among migrants to different environment

22. Type 2 Diabetes Pima Indians Gila River Reservation Type 2 Diabetes 50% 2% Schulz, 1996

24. Human Diseases Result from Gene-Environment Interactions “If all factors that determine disease are taken into account, then 100% of disease can be said to be inherited. Analogously, 100% of any disease is environmentally caused.” Kenneth Rothman, Modern Epidemiology, 1986

26. Value of Population-Based Samples • Enhance generalizability (and reduce bias) of study findings • Estimate gene frequencies and population risk parameters • Collect comparable case and control groups to minimize confounding • Obtain sufficient number of subjects to increase power to detect genes of small effect

27. Genetic and Environmental Factors in Alzheimer’s Disease Environment Genes Susceptibility Head trauma Vascular factors HSV-1 Total cholesterol Hypertension Susceptibility APOE-E 4 Alzheimer’s Disease Probabilistic -amyloid precursor Presenilin – 1 Presenilin – 2 Protective N.S.A.I.D.’s Estrogen Education Slooter & Van Duijn, 1997

28. Risk Factors and Impact of Selected Chronic Diseases Merikangas & Risch, 2003

29. Priorities for Genomics Research • Biologically valid phenotype • Knowledge regarding pathogenesis • High genetic attributable risk • Specific environmental factors have not been identified • Severe impact or high prevalence Merikangas & Risch, 2003

30. Priorities for Environmental Research • Specific environmental exposure(s) • Modifiable exposures • Exposures with high attributable risk Merikangas & Risch, 2003