While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.
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The authors are extremely grateful to Soren Germer, Ph.D. and his team at the New York Genome Center for performing the Illumina sequencing. We acknowledge financial support from the Human Frontier Science Program (SC); NIH research Grants AG042188 (GA), DK62429, DK062422, DK092235 (JHC), NS050487, NS060113 (LNC), AG021654, AG027734 (NB), MH089964, MH095458, MH084098 (TL), and CA121852 (computational infrastructure, IPe’er); NSF research grants 08929882 and 0845677 (IPe’er); Rachel and Lewis Rudin Foundation (HE); Northwell Health Foundation (TL); Brain & Behavior Foundation (TL); US-Israel Binational Science Foundation (TL, AD); LUNGevity Foundation (ZHG); New York Crohn’s Disease Foundation (IPeter); Edwin & Caroline Levy and Joseph & Carol Reich (SB); the Parkinson’s Disease Foundation (LNC); the Sharon Levine Corzine Cancer Research Fund (KO); and the Andrew Sabin Family Research Fund (KO).
Conflict of interest
The authors declare no competing financial interests.
Whole genome sequence data have been deposited at the European Genome-phenome Archive (EGA, http://www.ebi.ac.uk/ega/), which is hosted by the EBI, under accession code EGAS00001000664. Genotype data for target samples is available at The database of Genotypes and Phenotypes (dbGaP, https://www.ncbi.nlm.nih.gov/gap), under Accession number phs000448.v1.p1.
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Lencz, T., Yu, J., Palmer, C. et al. High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation. Hum Genet 137, 343–355 (2018). https://doi.org/10.1007/s00439-018-1886-z