Shuldiner, A. R. | Search bioRxiv

bioRxiv2017

Profiling and leveraging relatedness in a precision medicine cohort of 92,455 exomes

Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in-line with expectations given the underlying population and ascertainment approach. For example, we identified [~]66,000 close (first- and second-degree) relationships within DiscovEHR involving 55.6% of study participants. Our simulation results project that >70% of the cohort will be involved in these close relationships as DiscovEHR scales to 250,000 recruited individuals. We reconstructed 12,574 pedigrees using these relationships (including 2,192 nuclear families) and leveraged them for multiple applications. The pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious compound heterozygous mutations. Reconstructed nuclear families were critical for identifying 3,415 de novo mutations in [~]1,783 genes. Finally, we demonstrate the segregation of known and suspected disease-causing mutations through reconstructed pedigrees, including a tandem duplication in LDLR causing familial hypercholesterolemia. In summary, this work highlights the prevalence of cryptic relatedness expected among large healthcare population genomic studies and demonstrates several analyses that are uniquely enabled by large amounts of cryptic relatedness.

genomics↗

bioRxiv2017

Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes

Copy number variants (CNVs) are a substantial source of genomic variation and contribute to a wide range of human disorders. Gene-disrupting exonic CNVs have important clinical implications as they can underlie variability in disease presentation and susceptibility. The relationship between exonic CNVs and clinical traits has not been broadly explored at the population level, primarily due to technical challenges. We surveyed common and rare CNVs in the exome sequences of 50,726 adult DiscovEHR study participants with linked electronic health records (EHRs). We evaluated the diagnostic yield and clinical expressivity of known pathogenic CNVs, and performed tests of association with EHR-derived serum lipids, thereby evaluating the relationship between CNVs and complex traits and phenotypes in an unbiased, real-world clinical context. We identified CNVs from megabase to exon-level resolution, demonstrating reliable, high-throughput detection of clinically relevant exonic CNVs. In doing so, we created a catalog of high-confidence common and rare CNVs and refined population frequency estimates of known and novel gene-disrupting CNVs. Our survey among an unselected clinical population provides further evidence that neuropathy-associated duplications and deletions in 17p12 have similar population prevalence but are clinically under-diagnosed. Similarly, adults who harbor 22q11.2 deletions frequently had EHR documentation of neurodevelopmental/neuropsychiatric disorders and congenital anomalies, but not a formal genetic diagnosis (i.e., deletion). In an exome-wide association study of lipid levels, we identified a novel five-exon duplication within LDLR segregating in a large kindred with features of familial hypercholesterolemia. Exonic CNVs provide new opportunities to understand and diagnose human disease.

genomics↗