Population genomics in a disease targeted primary cell model (original) (raw)

  1. Elin Grundberg1,2,12,
  2. Tony Kwan1,2,12,
  3. Bing Ge2,
  4. Kevin C.L. Lam2,
  5. Vonda Koka2,
  6. Andreas Kindmark3,
  7. Hans Mallmin4,
  8. Joana Dias2,
  9. Dominique J. Verlaan1,2,5,
  10. Manon Ouimet5,
  11. Daniel Sinnett5,6,
  12. Fernando Rivadeneira7,8,
  13. Karol Estrada7,
  14. Albert Hofman8,
  15. Joyce M. van Meurs7,
  16. André Uitterlinden7,8,
  17. Patrick Beaulieu5,
  18. Alexandru Graziani5,
  19. Eef Harmsen2,
  20. Östen Ljunggren3,
  21. Claes Ohlsson9,
  22. Dan Mellström9,
  23. Magnus K. Karlsson10,
  24. Olle Nilsson4 and
  25. Tomi Pastinen1,2,11,13
  26. 1 Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada;
  27. 2 McGill University and Genome Québec Innovation Centre, Montréal H3A 1A4, Canada;
  28. 3 Department of Medical Sciences, Uppsala University, Uppsala 75185, Sweden;
  29. 4 Department of Surgical Sciences, Uppsala University, Uppsala 75185, Sweden;
  30. 5 Sainte-Justine University Health Center, Montréal H3T 1C5, Canada;
  31. 6 Department of Pediatrics, University of Montréal, Montréal H3T 1C5, Canada;
  32. 7 Department of Internal Medicine, Erasmus MC, Rotterdam 3015GE, The Netherlands;
  33. 8 Department of Epidemiology, Erasmus MC, Rotterdam 3015GE, The Netherlands;
  34. 9 Center for Bone Research at the Sahlgrenska Academy, Department of Internal Medicine, Göteborg University, Gothenburg 41345, Sweden;
  35. 10 Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Science, Lund University and Department of Orthopaedics, Malmö University Hospital, Malmö 20502, Sweden;
  36. 11 Department of Medical Genetics, McGill University, Montréal H3H 1P3, Canada
  37. ↵12 These authors contributed equally to this work.

Abstract

The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < ∼10−3) were tested for _cis_-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging _cis_-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong _cis_-effects on gene expression in HObs (P = 6 × 10−10 − 7 × 10−16) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (_P_combined = 5.6 × 10−5). The _cis_-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, _r_2 = 0.5, P = 2.6 × 10−15). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

Footnotes