Mark Daly
Associate Professor of Medicine, Harvard Medical School
Chief, Analytic and Translational Unit
Center for Human Genetic Research, Department of Medicine
Massachusetts General Hospital
Prioritizing and Interpreting Rare Variation & Exome Sequencing
Genomewide association studies have been highly successful at identifying numerous loci for common, complex disorders – yet for the vast majority, the lack of conclusive identification of the implicated gene and causal, functional variants has greatly limited conversion of these findings into biological insights and actionable therapeutic hypotheses. While exome sequencing offers a systematic approach to identifying specific functional alleles, the identification of ab initio robust findings from these studies has also been challenging. I will discuss emerging strategies for integrating the fine mapping of GWAS hits with parallel exome sequencing analyses to overcome some of these challenges. Further, the advantages of performing rare variation studies in isolated, bottlenecked populations, and inferences drawn about individual gene mutational tolerances from large population sequencing efforts will be employed to inform the interpretation of low frequency and rare variation in complex human disease, in much the same way these strategies are employed in Mendelian disease.
