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Plenary and Platform Abstracts American Society of Human Genetics 68th Annual Meeting PLENARY AND PLATFORM ABSTRACTS Abstract #'s Tuesday, October 16, 5:30-6:50 pm: 4. Featured Plenary Abstract Session I Hall C #1-#4 Wednesday, October 17, 9:00-10:00 am, Concurrent Platform Session A: 6. Variant Insights from Large Population Datasets Ballroom 20A #5-#8 7. GWAS in Combined Cancer Phenotypes Ballroom 20BC #9-#12 8. Genome-wide Epigenomics and Non-coding Variants Ballroom 20D #13-#16 9. Clonal Mosaicism in Cancer, Alzheimer's Disease, and Healthy Room 6A #17-#20 Tissue 10. Genetics of Behavioral Traits and Diseases Room 6B #21-#24 11. New Frontiers in Computational Genomics Room 6C #25-#28 12. Bone and Muscle: Identifying Causal Genes Room 6D #29-#32 13. Precision Medicine Initiatives: Outcomes and Lessons Learned Room 6E #33-#36 14. Environmental Exposures in Human Traits Room 6F #37-#40 Wednesday, October 17, 4:15-5:45 pm, Concurrent Platform Session B: 24. Variant Interpretation Practices and Resources Ballroom 20A #41-#46 25. Integrated Variant Analysis in Cancer Genomics Ballroom 20BC #47-#52 26. Gene Discovery and Functional Models of Neurological Disorders Ballroom 20D #53-#58 27. Whole Exome and Whole Genome Associations Room 6A #59-#64 28. Sequencing-based Diagnostics for Newborns and Infants Room 6B #65-#70 29. Omics Studies in Alzheimer's Disease Room 6C #71-#76 30. Cardiac, Valvular, and Vascular Disorders Room 6D #77-#82 31. Natural Selection and Human Phenotypes Room 6E #83-#88 32. Genetics of Cardiometabolic Traits Room 6F #89-#94 Wednesday, October 17, 6:00-7:00 pm, Concurrent Platform Session C: 33. Characterization of Structural Variation in Population Controls and Ballroom 20A #95-#98 Disease 34. Reanalysis of Sequencing Data to Increase Diagnostic Yield Ballroom 20BC #99-#102 35. Subclonal Somatic Mutations Ballroom 20D #103-#106 36. Diverse Approaches for Identifying Target Genes from GWAS Room 6A #107-#110 Results 37. From GWAS to Function in Cancer Room 6B #111-#114 Copyright © 2018 The American Society of Human Genetics. All rights reserved. 38. Insights from and into Mendelian Disorders of the Liver and Room 6C #115-#118 Pancreas 39. Scalable Tools to Enable Collaboration and Reproducible Room 6D #119-#122 Analyses 40. Genomic Testing: Strategies and Patient Perspectives Room 6E #123-#126 41. Therapeutic Development: Adding or Subtracting Room 6F #127-#130 Thursday, October 18, 9:00-10:30 am, Concurrent Platform Session D: 42. Advances in GWAS Analytical Methods Ballroom 20A #131-#136 43. Genomic Insights from Diverse Populations Ballroom 20BC #137-#142 44. Comprehensive Descriptions of Genetic Architecture of Rare Ballroom 20D #143-#148 Diseases 45. Learning from Genome Mutation Patterns Room 6A #149-#154 46. Neurodegenerative Disease: Revealing Disease Mechanisms Room 6B #155-#160 47. DNA Methylation in Human Disease Room 6C #161-#166 48. Genetic Disorders of Vision and Hearing Room 6D #167-#172 49. Emerging Omics Technologies Room 6E #173-#178 50. Discovery Studies of Cardiovascular and Metabolic Phenotypes Room 6F #179-#184 Thursday, October 18, 11:00 am-12:30 pm, Concurrent Platform Session E: 51. What are We Missing? Identification of Previously Ballroom 20A #185-#190 Underappreciated Mendelian Variants 52. Single Cell Approaches to Reveal Disease Biology Ballroom 20BC #191-#196 53. Expanding the Scope of Mendelian Randomization Ballroom 20D #197-#202 54. Genetics and Functional Insights into Schizophrenia Room 6A #203-#208 55. The Contribution of Structural Variation to Neurological Disorders Room 6B #209-#214 56. Leveraging GWAS Data with Other Data Types Room 6C #215-#220 57. New Genes, Old Genes, and Novel Functions in the Central Room 6D #221-#226 Nervous System 58. Skin and Bones: Mendelian Skeletal, Connective Tissue, and Room 6E #227-#232 Ectodermal Phenotypes 59. Genetic Variant Effects on Blood Lipids Room 6F #233-#238 Friday, October 19, 9:00-10:00 am, Concurrent Platform Session F: 65. Mutational Processes in Cancer Ballroom 20A #239-#242 66. Genetics of Cancer Therapy Response and Resistance Ballroom 20BC #243-#246 67. Genetic Architecture of Hematopoiesis Ballroom 20D #247-#250 68. Enhancers and Noncoding Regions Room 6A #251-#254 69. Using RNA-seq to Improve DNA Sequence Interpretation Room 6B #255-#258 70. Cell Types, States, and Networks Room 6C #259-#262 71. Genetic Effects on Pregnancy and Fetal Health Room 6D #263-#266 72. Translating Cardiovascular Genetics to Patient Care Room 6E #267-#270 73. Therapeutic Development: Modulating Cellular Effectors Room 6F #271-#274 Friday, October 16, 5:00-6:20 pm: 87. Featured Plenary Abstract Session I Hall C #275-#278 Friday, October 16, 6:20-7:20 pm: 88. Late-breaking Abstract Session I Hall C #3568-#3570 Copyright © 2018 The American Society of Human Genetics. All rights reserved. Saturday, October 20, 8:30-9:30 am, Concurrent Platform Session G: 89. Transcriptome Alterations in Cancer Ballroom 20A #279-#282 90. The Non-coding Genome and Disease Ballroom 20BC #283-#286 91. Biases of Polygenic Risk Scores Ballroom 20D #287-#290 92. Potential Genetic and Epigenetic Therapies of Disease Room 6A #291-#294 93. Investigating 3D Genome Structure Room 6B #295-#298 94. Importance of Isoform Expression in Variant Interpretation Room 6C #299-#302 95. Cancer Genomic Testing: Uncertainty and Decision Making Room 6D #303-#306 96. Leveraging The Cancer Genome Atlas Room 6E #307-#310 97. The Genetics and Genomics of Epilepsy Room 6F #311-#314 Saturday, October 20, 9:45-11:15 am, Concurrent Platform Session H: 98. Fine-mapping Using Statistical and Functional Tools Ballroom 20A #315-#320 99. Genetic and Epigenetic Effects on the Transcriptome Ballroom 20BC #321-#326 100. Understanding the Brain with Computational Genomics Ballroom 20D #327-#332 101. Novel Approaches for Conducting Genome-wide Association Room 6A #333-#338 Studies 102. Increasing Functional Resolution Through Single Cell Analysis Room 6B #339-#344 103. Evaluating the Yield of Genetic Testing in Diverse Settings Room 6C #345-#350 104. Discoveries in Syndromic and Non-syndromic Congenital Heart Room 6D #351-#356 Disease 105. Human Reproduction and Fertility Room 6E #357-#362 106. Genetics of Growth and Lifespan Room 6F #363-#368 Saturday, October 20, 11:40 am-1:00 pm: 108. Featured Plenary Abstract Session I Hall C #369-#372 Copyright © 2018 The American Society of Human Genetics. All rights reserved. ASHG 2018 Abstracts 1 1 2 From GWAS to function: Comprehensive integrated genomic perturba- Incidence of uniparental disomy in 2 million individuals from the 23and- tion to reveal molecular mechanisms of trait associations. M.A. Cole1,2,3, Me database. P. Nakka1,2, K. McManus3, A. O'Donnell-Luria4,5, U. Francke6, A. Mousas5,6, Y. Wu1,2,3, J. Zeng1,2,3, Q. Yao1,2,3,4, D. Vinjamur1,2,3, R. Kurita7, Y. Na- J. Mountain3, S. Ramachandran1,2, F. Sathirapongsasuti3, 23andMe Research kamura7,8, L. Pinello3,4, G. Lettre3,4, D.E. Bauer1,2,3. 1) Boston Children's Hospital, Team. 1) Center for Computational Molecular Biology, Brown University, Provi- Boston, MA; 2) Dana-Farber Cancer Institute, Boston, MA; 3) Harvard Medical dence, RI; 2) Ecology and Evolutionary Biology, Brown University, Providence, School, Boston, MA; 4) Massachusetts General Hospital, Boston, MA; 5) Uni- RI; 3) 23andMe, Inc., Mountain View, CA; 4) Boston Children’s Hospital, Bos- versite de Montreal, Montreal, Quebec, Canada; 6) Montreal Heart Institute, ton, MA; 5) Broad Institute of MIT and Harvard, Cambridge, MA; 6) Stanford Montreal, Quebec, Canada; 7) RIKEN BioResource Center, Tsukuba, Ibaraki, University, Palo Alto, CA. Japan; 8) . 7 University of Tsukuba, Tsukuba, Ibaraki, Japan. Uniparental Disomy (UPD) is the inheritance of both homologs of a chromo- Discovery of molecular mechanisms responsible for trait associations is some from one parent with no representative copy from the other. UPD can hampered by difficulty in identifying causal variants. Typical assays of genetic cause clinical phenotypes by disrupting parent-specific genomic imprinting, function are low throughput or evaluate sequences in heterologous ectopic or by unmasking recessive alleles in blocks of homozygosity on the affected settings. Genome editing enables perturbation of trait-associated sequences chromosome. Though over 3,300 clinical cases of UPD have been collected within relevant genomic, chromatin and cellular context. Here we perform com- to date, our understanding of UPD is limited to chromosomes on which UPD prehensive analysis of genetic variants associated with red blood cell traits by causes clinical presentation. In particular, incidence of UPD, its subtypes, and pooled CRISPR screening. We performed a genome-wide knockout screen their phenotypic consequences are very poorly characterized in the general in immortalized erythroid precursors (HUDEP-2 cells) to define functional population. To address this gap, we analyze instances of UPD in consented erythroid genes required for cell growth or differentiation. We evaluated 952 research participants from the personal genetics company 23andMe, Inc., loci associated with nine red blood cell traits (Astle et al, Cell 2016) comprising whose database consisted of SNP data from over 2 million individuals. We 24,843 SNPs. We linked 28.9% of these SNPs to genes by at least one of estimate identity-by-descent (IBD) between 290,927 parent-child duos and four routes: sharing topological associated domain, physical proximity (<20 identify 49 instances of UPD, corresponding to an incidence rate of 1 in 4,000 kb), long-range chromatin interaction, or eQTL with a functional erythroid births for UPD in the general population. In the 23andMe database, UPD gene. We designed ~5 sgRNAs per SNP requiring cleavage within 50 bp and cases occur most frequently on chromosomes 16, 21 and 22. In contrast, ex- exceeding an off-target score threshold, resulting in 32,710 sgRNAs testing isting clinical cases cluster on chromosomes 6, 7, 11, 14, and 15, which each 5,592 SNPs at 481 loci.
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