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High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation

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Abstract

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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Acknowledgements

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).

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Author notes

  1. Todd Lencz and Jin Yu contributed equally.

Authors and Affiliations

  1. Departments of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11550, USA

    Todd Lencz

  2. Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY, 11004, USA

    Todd Lencz & Jin Yu

  3. Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA

    Todd Lencz & Jin Yu

  4. Department of Computer Science, Columbia University, 500 W 120th St, New York, NY, 10027, USA

    Cameron Palmer & Itsik Pe’er

  5. Faculty of Medicine, Braun School of Public Health, Hebrew University of Jerusalem, Ein Kerem, 9112102, Jerusalem, Israel

    Shai Carmi

  6. Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA

    Danny Ben-Avraham, Nir Barzilai, Harry Ostrer & Gil Atzmon

  7. Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA

    Danny Ben-Avraham, Nir Barzilai & Gil Atzmon

  8. Department of Neurology, Beth Israel Medical Center, New York, NY, 10003, USA

    Susan Bressman

  9. Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, 91904, Jerusalem, Israel

    Ariel Darvasi

  10. Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, New York, NY, 10029, USA

    Judy H. Cho

  11. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, New York, NY, 10029, USA

    Judy H. Cho, Zeynep H. Gümüş, Robert Klein & Inga Peter

  12. Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Ave, New York, NY, 10032, USA

    Lorraine N. Clark

  13. Taub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, 1150 St Nicholas Ave, New York, NY, 10032, USA

    Lorraine N. Clark

  14. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, New York, NY, 10029, USA

    Zeynep H. Gümüş, Robert Klein & Inga Peter

  15. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA

    Vijai Joseph & Kenneth Offit

  16. Departments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, NY, USA

    Steven Lipkin

  17. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA

    Kenneth Offit

  18. Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA

    Harry Ostrer

  19. Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Laurie J. Ozelius

  20. Department of Human Biology, Haifa University, Haifa, Israel

    Gil Atzmon

  21. Center for Computational Biology and Bioinformatics, Columbia University, 1130 St Nicholas Ave, New York, NY, 10032, USA

    Itsik Pe’er

Authors
  1. Todd Lencz
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  2. Jin Yu
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  3. Cameron Palmer
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  4. Shai Carmi
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  20. Itsik Pe’er
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Contributions

TL and IP led the analysis, and led the writing of the manuscript. JY, CP, and SC conducted the primary analyses. TL led the funding of the study. TL, AD, GA, DB, NB, and LNC provided samples and conducted lab work. TL, IP, NB, SB, AD, JHC, LNC, ZHG, VJ, RK, SL, KO, HO, LJO, IP, and GA initiated and designed the study, and provided funding.

Corresponding authors

Correspondence to Todd Lencz or Itsik Pe’er.

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Conflict of interest

The authors declare no competing financial interests.

Accession codes

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

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