Large-scale whole-genome sequencing of the Icelandic population (original) (raw)

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Acknowledgements

We thank all the participants in this study. This study was performed in collaboration with Illumina.

Author information

Author notes

1. Daniel F Gudbjartsson and Hannes Helgason: These authors contributed equally to this work.

Authors and Affiliations

1. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
   Daniel F Gudbjartsson, Hannes Helgason, Sigurjon A Gudjonsson, Florian Zink, Asmundur Oddson, Arnaldur Gylfason, Gisli Magnusson, Bjarni V Halldorsson, Eirikur Hjartarson, Gunnar Th Sigurdsson, Simon N Stacey, Michael L Frigge, Hilma Holm, Jona Saemundsdottir, Hafdis Th Helgadottir, Hrefna Johannsdottir, Solveig Gretarsdottir, G Bragi Walters, Thorunn Rafnar, Asgeir Sigurdsson, Gyda Bjornsdottir, Hakon Gudbjartsson, Olafur Th Magnusson, Augustine Kong, Gisli Masson, Unnur Thorsteinsdottir, Agnar Helgason, Patrick Sulem & Kari Stefansson
2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
   Daniel F Gudbjartsson, Hannes Helgason, Hakon Gudbjartsson & Augustine Kong
3. Bioinformatics Research Centre, Aarhus University, C.F. Mollers Alle, Aarhus, Denmark
   Soren Besenbacher
4. Institute of Biomedical and Neural Engineering, Reykjavík University, Reykjavík, Iceland
   Bjarni V Halldorsson
5. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
   Hilma Holm
6. Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland
   Gunnlaugur Sigfusson
7. Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland
   Gudmundur Thorgeirsson, Bjarni Thjodleifsson & David O Arnar
8. Faculty of Medicine, University of Iceland, Reykjavik, Iceland
   Gudmundur Thorgeirsson, Einar S Bjornsson, Sigurdur Olafsson, Thora Steingrimsdottir, Jon G Jonasson, David O Arnar, Unnur Thorsteinsdottir & Kari Stefansson
9. Department of Internal Medicine, Akureyri Hospital, Akureyri, Iceland
   Jon Th Sverrisson
10. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
    Einar S Bjornsson, Sigurdur Olafsson, Hildur Thorarinsdottir & Asgeir Theodors
11. Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland
    Thora Steingrimsdottir & Thora S Gudmundsdottir
12. Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland
    Jon G Jonasson
13. Icelandic Cancer Registry, Reykjavik, Iceland
    Jon G Jonasson
14. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Jon J Jonsson
15. Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland
    Jon J Jonsson
16. Department of Pediatrics, Section of Child Neurology, The Children's Hospital of Reykjavik, Landspitali University Hospital, Reykjavik, Iceland
    Olafur Thorarensen & Petur Ludvigsson
17. Icelandic Medical Center (Laeknasetrid), Laboratory in Mjodd (RAM), Reykjavik, Iceland
    Gudmundur I Eyjolfsson
18. Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland
    Olof Sigurdardottir
19. Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland
    Isleifur Olafsson
20. Department of Anthropology, University of Iceland, Reykjavik, Iceland
    Agnar Helgason

Authors

1. Daniel F Gudbjartsson
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2. Hannes Helgason
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3. Sigurjon A Gudjonsson
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4. Florian Zink
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5. Asmundur Oddson
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6. Arnaldur Gylfason
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7. Soren Besenbacher
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8. Gisli Magnusson
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9. Eirikur Hjartarson
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10. Gunnar Th Sigurdsson
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11. Simon N Stacey
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12. Michael L Frigge
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13. Hilma Holm
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14. Jona Saemundsdottir
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15. Hafdis Th Helgadottir
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16. Hrefna Johannsdottir
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17. Gunnlaugur Sigfusson
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18. Jon Th Sverrisson
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19. Solveig Gretarsdottir
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20. G Bragi Walters
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21. Thorunn Rafnar
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22. Bjarni Thjodleifsson
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23. Einar S Bjornsson
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24. Sigurdur Olafsson
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25. Hildur Thorarinsdottir
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26. Thora Steingrimsdottir
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27. Thora S Gudmundsdottir
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28. Asgeir Theodors
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29. Jon G Jonasson
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30. Asgeir Sigurdsson
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31. Gyda Bjornsdottir
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32. Jon J Jonsson
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33. Olafur Thorarensen
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34. Petur Ludvigsson
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35. Hakon Gudbjartsson
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36. Gudmundur I Eyjolfsson
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37. Olof Sigurdardottir
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38. Isleifur Olafsson
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39. David O Arnar
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40. Olafur Th Magnusson
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41. Augustine Kong
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42. Gisli Masson
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43. Unnur Thorsteinsdottir
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44. Agnar Helgason
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45. Patrick Sulem
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46. Kari Stefansson
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Contributions

D.F.G., H. Helgason, S.A.G., F.Z., D.O.A., O.T.M., G. Masson, A.H., P.S. and K.S. wrote the initial draft of the manuscript. D.F.G., H. Helgason, S.A.G., F.Z., A.O., G. Magnusson, B.V.H., E.H., G.T.S., S.N.S., M.L.F., A.K., G. Masson and P.S. analyzed the data. D.F.G., H. Helgason, S.A.G., F.Z., A.G., S.B., H.G. and G. Masson created methods for analyzing the data. S.N.S., H. Holm, J.S., H.T.H., H.J. and O.T.M. performed the experiments. H. Holm, G.S., G.T., J.T.S., S.G., G.B.W., T.R., B.T., E.S.B., S.O., H.T., T.S., T.S.G., A.T., J.G.J., A.S., G.B., J.J.J., O.T., P.L., G.I.E., O.S., I.O. and D.O.A. collected the samples and information. D.F.G., D.O.A., G. Masson, U.T., A.H., P.S. and K.S. designed the study.

Corresponding authors

Correspondence toDaniel F Gudbjartsson or Kari Stefansson.

Ethics declarations

Competing interests

The authors affiliated with deCODE Genetics are employed by the company, which is owned by Amgen, Inc: D.F.G., H. Helgason, S.A.G., F.Z., A.O., A.G., G. Magnusson, B.V.H., E.H., G.T.S., S.N.S., M.L.F., H. Holm, J.S., H.T.H., H.J., S.G., G.B.W., T.R., A.S., G.B., H.G., O.T.M., A.K., G. Masson, U.T., A.H., P.S. and K.S.

Integrated supplementary information

Supplementary Figure 1 Sequencing depth of the 2,636 sequenced Icelanders.

Supplementary Figure 2 Overview of sequence alignment and variant calling.

Supplementary Figure 3 Overview of the process for sequence variant imputation.

Supplementary Figure 5 Comparison of imputed and chip genotypes.

Shown is the fraction of the 28,204 SNPs identified in exons and splice regions and present on SNP chips that have _r_2 > 0.8, 0.9 and 0.99 between the imputed and chip genotypes as a function of their derived allele frequency (DAF).

Supplementary Figure 6 The five pedigrees containing the eight homozygous carriers of c.234delC in MYL4.

Symbols for homozygous carriers are colored black. Symbols for deceased individuals are stricken through with a forward-leaning line. Symbols for individuals who have not been genotyped directly are stricken through with a backward-leaning line. Under each individual are up to five lines containing information about the individual. First appear an identifier, consisting of a pedigree name (f1–f5), the generation of the individual in roman numerals and an enumerator within the generation. Second appear the individual’s year of birth and, if appropriate, the individual’s year of death. Third appears the individual’s c.234delC genotype, where D and W denote directly genotyped deletion and wild-type alleles, respectively, and d and w denote in silico genotypes inferred from the genotypes of relatives. The order of the alleles indicates the parent of origin, where the first allele comes from the father and the second allele comes from the mother, except for the three cases for whom parent of origin could not be assigned: f2-I:1, f2-I:2 and f3-I:2. Fourth appear an indication of whether the individual has been diagnosed with AF and the age at onset after the @ sign. Fifth appear the presence of other relevant phenotypes: sick sinus syndrome (SSS), pacemaker implantation (PM) and sudden cardiac death (SCD).

Supplementary Figure 7 The transmission of chromosome 17 through pedigree f-2.

The transmission of the founding couple of pedigree f-2 can be reconstructed on the basis of the expected values for meiotic transmissions of chromosome 17. The horizontal red lines indicate the position of c.234delC in MYL4, and the small red square surrounding the line indicates the region around c.234delC shared identically by decent by the founding couple. The length of this interval is estimated to be 3.3 cM. The first and last 10 cM of the chromosome have been truncated. The sisters f2-II:6 and f2-II:9 are imputed to be carrying c.234delC on their paternal chromosome on the basis of the chromosomal region around the deletion having been transmitted to their children (dark blue). There is no clear transmission of either sister’s maternal chromosomal region around the deletion to one of her children (although f2-III:3 may have inherited her mother’s paternal chromosome, but a crossover occurred in the region around c.234delC where f2-III:3 is homozygous). However, for both sisters, the maternal chromosome carrying the deletion (light blue) was transmitted to an offspring at regions on both sides of MYL4 (to f2-III:2 and f2-III:4) such that, unless a double crossover occurred around MYL4, they both carry c.234delC on their maternal chromosome.

Supplementary Figure 8 The families of the BVVL cases.

Shown are birth years and genotypes at the SLC52A2 mutation, where W denotes the wild-type allele and M denotes the mutated allele. Symbols for cases are colored black, and the symbols corresponding to the two siblings of case 4 who died early are colored gray. A forward slash indicates that the individual is deceased, and a backward slash indicates that an SLC52A2 genotype is not available for that individual.

Supplementary Figure 9 The effect of the filtering steps on the number of sequence variants that are candidates for causing BVVL syndrome in the two sisters.

The occurrence of a rare syndrome such as BVVL in two sisters suggests that it is caused by a rare genotype with high penetrance. We therefore restricted our search to LoF and MODERATE-impact variants. The sisters are affected but neither parent is, which suggests an autosomal recessive mode of inheritance. Allelic frequency over 2% would dictate a homozygous frequency of over 1 in 2,500, which would be too high for BVVL syndrome. This brought the number of potential variants down to 3 from 147. This would not have been possible using non-Icelandic resources such as ESP, as 4 of the 147 variants are not present in the database. We note that crude filtering, such as removing all variants present in public databases, would result in removing the causative sequence variant. This left us with three correlated MODERATE-impact variants on chromosome 8q24.3: p.Leu339Pro (rs148234606) in SLC52A2, p.Gln931Arg in OPLAH and c.2982C>T in CPSF1. No one was imputed to be homozygous for the SLC52A2 variant in the set of additional chip-typed Icelanders, whereas 5 and 19 Icelanders were imputed to be homozygous for the OPLAH and CPSF1 SNPs, respectively. No early deaths were reported among these homozygous carriers, and the oldest homozygous carriers reached ages 77 and 89 years for OPLAH and CPSF1, respectively, which is inconsistent with diagnosis of BVVL, as only 1 of 77 reported BVVL syndrome cases has lived past 60 years36,37,38,39,40,41,42,43,44.

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Gudbjartsson, D., Helgason, H., Gudjonsson, S. et al. Large-scale whole-genome sequencing of the Icelandic population.Nat Genet 47, 435–444 (2015). https://doi.org/10.1038/ng.3247

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• Received: 17 February 2014
• Accepted: 13 February 2015
• Published: 25 March 2015
• Issue Date: May 2015
• DOI: https://doi.org/10.1038/ng.3247