• Return of Results: Genomic Medicine Projects: 3,700 patients enrolled in longitudinal protocols (including 663 eMERGE PGx). 512 total providers are enrolled, educated, and surveyed. GUARDD: 579 enrolled so far (out of 2,050 goal). GUARDD CDS activity is approaching 1,000 alerts. PGx: Close to 900 sequenced, 660 returned results, study is completed as of November 2015. There is a 74.4% acceptance rate of PGx projects at Mount Sinai. Incidental findings from PGRNSeq: Out of 663 individuals, 4 were found with known or likely pathogenic variants in ACMG genes. • Mount Sinai looks to continue their community and provider engagement through the building of large cohorts. They will continue genotyping sequencing Illumina MEGA array for all BioMe participants and look to whole genome sequence approximately 5,000 participants with two partners. The genomic medicine research in primary care and medical subspecialties will also continue. Evolving Ancestry: The Shift in Individual Ancestry Composition over Time – Tracy McGregor • The group evaluated ancestry informative markers and estimated proportions of racial ancestry with categorical race in a cohort of approximately 35,000 from BioVU, as recorded in the electronic health record. • In individuals born from 1905 – 2010, there is increasing admixture in the Hispanic-Latino, Asian, and White populations. Older Black populations were more admixed and now the population is slowly admixing again. • Individuals identified as White in the electronic health record have become more genetically admixed over time. The mean fractions of European ancestry have decreased from over 98% for all cohorts by decade of birth through the 1980’s to 95.7% and 90.0% for the cohorts born in the 2000’s and 2010’s, respectively. • Data indicate that younger cohorts of individuals exhibit higher levels of heterogeneity than older cohorts, particularly within those identified as White. There was also increasing heterozygosity over time, with more rapid increases in younger subjects, implying increasing rates of migration of alleles between racial groups over time. Genomics Workgroup Update – David Crosslin & Patrick Sleiman • The special issue of Frontiers in Genetics now has over 42,000 views. • The workgroup ongoing structural variation discovery projects include: RBC indices (Mayo), Global burden (Penn State), PheWAS (VU,GH/UW), PheWAS Pediatrics (CCHMC/BCH), WBC and differential (GH/UW), and Homozygous deletions (CHOP). • The following GWAS are completed: BMI-Obesity, Autism, Billrubin-LFT, Asthma, GERD, Atopic Dermatitis, Extreme Obesity, Ocular HTN, AMD, Glaucoma, VTE, Apolipoprotein L1 and HTN, Diabetic Hypertensive CKD, Diverticular disease, Shingles, ACE-I Cough, Statins for MACE • The workgroup is still trying to establish a concept sheet with ENCODE collaboration. The workgroup is also collaborating with Exome Chip project, which includes Geisinger, Mayo, and Group Health. • The workgroup is changing their focus from discovery to implementation as it looks to eMERGE III. CHOP Site Report – Hakon Hakonarson • All major pediatric and adult diseases are represented in the Center for Applied Genomics (CAG) biobank, including rare diseases; there are more than 70,000 children and 12,000+ adults. All participants consent to prospective genetic analyses. Children are re-consented when 18 years (>90% success). • Five phenotype algorithms were led at CHOP and CHOP has participated in multiple validations. Asthma severity was validated and near ready for publication. • 1,606 total PheWAS codes were translated in the phenotype table. Demographically, the numbers are comparable between European Americans and African Americans, with several years of follow up. • PheWAS on rs6967330: cases were defined as subjects with multiple hospitalizations for asthma exacerbations within 6 months between ages of 2–6. rs6967330 encodes an amino acid change in the CDHR3 protein. A recent study showed that the disease associated with a variant of the CDHR3 protein enhanced infection rates of rhinovirus C, which leads to asthma exacerbation.