NIAAA Extramural Advisory Board Report “Etiology of Risk: Genes & Environment”

1. NIAAA Extramural Advisory Board Report “Etiology of Risk: Genes & Environment” August 30 -31, 2004 Fulton T. Crews UNC Chapel Hill NIAAA Council Meeting September 9, 2004

2. PARTICIPANT LIST Etiology of Risk: Genes & Environment (ERGE) Team Co Leaders Kendall Bryant Zhaoxia Ren Invited Experts Lindon Eaves Deborah Hasin Victor Hesselbrock (rep. RSA) Matt McGue Research Strategies Committee (RSC) Ting-Kai Li Stephen Long Faye Calhoun Mark Goldman Kenneth Warren Lorraine Gunzerath Special Consultants Lorraine Gunzerath Ellen Witt Extramural Advisory Board (EAB) John Crabbe Bankole Johnson Fulton Crews (Chair) Peter Monti Cindy Ehlers Kenneth Sher (rep. NIAAA Adv. Council) Tom Greenfield Linda Spear Andrew Heath Section Contributors Lisa Neuhold Lindsey Grandison Marcia Scott Robert Freeman Kendall Bryant Zhaoxia Ren Ke Xu Charlene LeFauve Antonio Noronha ERGE Team Members Megan Adamson Nanwei Cao Deidra Roach Diana Urbanas Tina Vanderveen Dorita Sewell

3. Charge from NIAAA Director • Review Gene and Environment portfolios to ensure responsiveness to emerging trends examining interactions. • Review scientific models of interactions within NIAAA and with NIH institutes and agencies. • Examine other sources of information. Identify new perspectives. • Help to define a 5-year vision of G x E research portfolio for NIAAA.

4. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS The committee reached consensus that the field is not ready for large scale studies in gene X environment interactions in humans at this time. However it was recommended that the following issues needed attention prior to the development of clinical studies in this area. Identification of specific genes related to alcohol dependence vs drug dependence vs general susceptibility to psychiatric disorders. 2. Better characterization of relevant phenotypes of AUD in humans and animals using well thought out strategies. 3. Identifying the most important environmental factors in humans and animals. 4. Add environmental measures to existing genetic studies where genotyping has already been accomplished. 5. Determine how development interacts with G X E interactions in humans and animals. 6. Develop a roadmap for studies in G X E that would address issues such as design and development of relevant mathematical methods to detect effects, so G X E interactions can be correctly identified and assessed.

5. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS • 1. Identification of specific genes related to alcohol dependence vs drug dependence vs general susceptibility to psychiatric disorders. Studies should continue identifying genes in human and animal studies, as well as identify pleiotrophic and epistatic effects. It is important to understand genetic background in animals and ethnic differences in humans as they interact with select genes. Determining whether the QTLs and genes found in animals are similar to what has been identified in human studies is recommended. Determine if gene expression studies in animals parallel any of the findings in humans.

6. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS • 2. Better characterization of relevant phenotypes of AUD in humans and animals using well thought out strategies. Identify phenotypes that translate between humans and animals.

7. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS • 3. Identifying the most important environmental factors in humans and animals.Identify or develop instruments that can survey environmental factors in humans. Explore the effects of early life experiences and rearing environments in animals on phenotypic and gene expression.

8. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS • 4. Add environmental measures to existing genetic studies where genotyping has already been accomplished.Add genotyping to particularly informative studies where there are also efforts to characterize the environment. Determine how G X E can be indexed in treatment studies and normal “aging out” of drinking, determine what interactions are optimal for recovery from AUDs.

9. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS 5. Determine how development interacts with G X E interactions in humans and animals. It seems likely that exposure to specific environments may be more potent on gene expression during certain times of development such as prenatal, early post natal, and up to early adulthood. Also “environment” may include early exposure to alcohol, nicotine and other drugs.

10. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS 6. Develop a roadmap for studies in G X E that would address issues such as design and development of relevant mathematical methods to detect effects, so G X E interactions can be correctly identified and assessed.

11. EAB RECOMMENDATIONS FOR GENE X ENVIRONMENT INTERACTIONS The committee reached consensus that the field is not ready for large scale studies in gene X environment interactions in humans at this time. However it was recommended that the following issues needed attention prior to the development of clinical studies in this area. Identification of specific genes related to alcohol dependence vs drug dependence vs general susceptibility to psychiatric disorders. 2. Better characterization of relevant phenotypes of AUD in humans and animals using well thought out strategies. 3. Identifying the most important environmental factors in humans and animals. 4. Add environmental measures to existing genetic studies where genotyping has already been accomplished. 5. Determine how development interacts with G X E interactions in humans and animals. 6. Develop a roadmap for studies in G X E that would address issues such as design and development of relevant mathematical methods to detect effects, so G X E interactions can be correctly identified and assessed.