1. The application of genome-wide association studies of aging in a patient-driven clinical trial outline Melanie Swan, Aaron Vollrath, Cindy Chen & Raymond McCauley, DIYgenomics, Palo Alto, CA USA melanie@DIYgenomics.org +1.415.505.4426 www.DIYgenomics.org/aging_poster.ppt Background The rapidly decreasing cost of whole genome sequencing could soon make the Personal Genome a reality for large numbers of individuals wanting access to and interpretation of their genomic information. Already the accessibility of this information is providing an impetus for patient-driven research. Though the advent of the truly personal genome, whereby everyone has access to their entire genomic data at an affordable price is not yet here, a number of options exist for individuals to obtain genotyping data from consumer genomic services. Costs range from $400-$2,000 for genotyping services to $20,000 for whole human genome sequencing for consumers. As proof of principle of a patient-driven clinical trial using personal genomic data in the form of identified variants, this study utilizes published data from genome-wide association studies (GWAS) to link genes and variants to a variety of biomarkers associated with human aging. The study outline takes into consideration GWAS results for critical aspects of aging including the inability to adequately regulate glucose levels, the decline of the immune system, ineffective catabolism, shortening of telomeres, and defects in lipoprotein metabolism. Genotyping data for a group of twenty citizen scientists is reviewed and can be further integrated with phenotypic measures of aging (including blood pressure, cholesterol, BMI, VO2 max, erythrocyte glycosylation, LDL particle size, telomere length, and lymphocyte growth rate), and used as the basis for proposed personalized interventions. Citizen-science contributed biobanks and databases are examined as a resource for the immediate, cost- effective, and large-scale application of research studies. Figure 1 These ~thousand variants associated with aging and their corresponding phenotypic measures provide the start of a comprehensive program for personal aging measurement and intervention. There are two kinds of intervention, traditional solutions and novel solutions. Traditional solutions consist of the usual condition management through diet, exercise, vitamins, and pharmaceuticals. Novel interventions consist of a variety of emerging solutions, many of which are speculative. Some of these include a crosslink breakers supplement to improve systolic hypertension (Zieman Journal of Hypertension 2007), brain fitness programs and mid-life cholesterol management for Alzheimer’s disease, TA-65 telomerase activation (TA Sciences) for telomere length management, resistance weight lifting for sarcopenia, interval training and aerobic exercise for VO2 max improvement, and blood-based assays for early detection and response to rheumatoid arthritis (Swanson Nat Rev Rheumatol 2009), macular degeneration (MacuCLEAR), and kidney and liver disease. Conclusion An urgent contemporary objective in public health is to implement preventive medicine. Tools are needed for personalized genome interpretation, and the meaningful integration of multiple health data streams: various levels of genomic and phenotypic data, and as they become available, environmental, microbiome, and other data. The large-scale open platforms of citizen science biobanks could be ideal for crowdsourced longitudinal data collection, targeted patient recruitment, and the conduct of a new generation of health research studies. Figure 5 Figure 2 Figure 4 Figure 3 Methodology The DIYgenomics study design methodology has three steps: identify strongly associated genomic variants for specific conditions, find corresponding phenotypic biomarkers, and establish corresponding interventions to the extent possible. Direct-to- consumer (DTC) genomic services cover some aging conditions. These data were included and supplemented with a more recent and exhaustive self-curation of GWAS. Self-curated GWAS references are cited; DTC references are available at DIYgenomics.org under ‘Health Risk.’ Approximately half of the SNPs identified in DTC and DIYgenomics curation are available for analysis in 23andme genotyping files. The five categories of aging-related GWAS are presented in Figures 1-5: aging-specific GWAS, diabetes, lipids, and metabolic disease, catabolism (waste break-down) and other, heart disease and blood operations, and cancer. As illustrated in Figure 1, the best-known processes of aging are not yet extensively covered in human GWAS, for example insulin/IGF-1 signaling pathways, inflammation, mitochondrial dysfunction, reactive oxygen species generation, cell cycle, stem cell generation, and immune response. Other areas such as diabetes and adiposity (Figure 2) have broader coverage and continue to be the focus of recent significant findings of novel loci. New cancer studies (Figure 5) have been more rare, and it is not necessary to supplement DTC curation. We would like to acknowledge review feedback from Lorenzo Albanello, Mark Hamalainen, and Anne and Gary Hudson. DIYgenomics is a non-profit research organization coordinating patient-driven clinical trials and providing personal genome data applications for 20 health conditions and 250 pharmaceutical drugs at http://www.DIYgenomics.org.http://www.DIYgenomics.org Acknowledgements Discussion 1. Aging-specific GWAS3. Catabolism (waste break-down) and other 5. Cancer 2. Diabetes, lipids, and metabolic disease 4. Heart disease and blood operations