Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants

Molecular Psychiatry volume 18, pages 340–346 (2013)Cite this article

Subjects

Abstract

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, Pbonferroni<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Egger G, Liang G, Aparicio A, Jones PA . Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457–463.

    Article  CAS  Google Scholar 

  2. Park PJ . Epigenetics meets next-generation sequencing. Epigenetics 2008; 3: 318–321.

    Article  Google Scholar 

  3. Schumacher A, Kapranov P, Kaminsky Z, Flanagan J, Assadzadeh A, Yau P et al. Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res 2006; 34: 528–542.

    Article  CAS  Google Scholar 

  4. Feinberg AP . Phenotypic plasticity and the epigenetics of human disease. Nature 2007; 447: 433–440.

    Article  CAS  Google Scholar 

  5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY . Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23: 185–188.

    Article  CAS  Google Scholar 

  6. Gamazon ER, Zhang W, Konkashbaev A, Duan S, Kistner EO, Nicolae DL et al. SCAN: SNP and copy number annotation. Bioinformatics 2010; 26: 259–262.

    Article  CAS  Google Scholar 

  7. Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ . Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 2010; 6: e1000888.

    Article  Google Scholar 

  8. Nica AC, Montgomery SB, Dimas AS, Stranger BE, Beazley C, Barroso I et al. Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 2010; 6: e1000895.

    Article  Google Scholar 

  9. Zhang D, Cheng L, Badner JA, Chen C, Chen Q, Luo W et al. Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet 2010; 86: 411–419.

    Article  CAS  Google Scholar 

  10. Liu C, Cheng L, Badner JA, Zhang D, Craig DW, Redman M et al. Whole-genome association mapping of gene expression in the human prefrontal cortex. Mol Psychiatry 2010; 15: 779–784.

    Article  CAS  Google Scholar 

  11. Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W et al. Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 2009; 14: 755–763.

    Article  CAS  Google Scholar 

  12. Smith EN, Koller DL, Panganiban C, Szelinger S, Zhang P, Badner JA et al. Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genet 2011; 7: e1002134.

    Article  CAS  Google Scholar 

  13. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

  14. Kato T, Iwamoto K, Kakiuchi C, Kuratomi G, Okazaki Y . Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders. Mol Psychiatry 2005; 10: 622–630.

    Article  CAS  Google Scholar 

  15. Petronis A . Epigenetics and bipolar disorder: new opportunities and challenges. Am J Med Genet C Semin Med Genet 2003; 123C: 65–75.

    Article  Google Scholar 

  16. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR . MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010; 34: 816–834.

    Article  Google Scholar 

  17. Li Y, Willer C, Sanna S, Abecasis G . Genotype imputation. Annu Rev Genomics Hum Genet 2009; 10: 387–406.

    Article  CAS  Google Scholar 

  18. Johnson WE, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8: 118–127.

    Article  Google Scholar 

  19. Leek JT, Storey JD . Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 2007; 3: 1724–1735.

    Article  CAS  Google Scholar 

  20. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  21. Gamazon ER, Nicolae DL, Cox NJ . A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci. PLoS Genet 2011; 7: e1001292.

    Article  CAS  Google Scholar 

  22. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106: 9362–9367.

    Article  CAS  Google Scholar 

  23. Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF et al. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 2011; 12: R10.

    Article  CAS  Google Scholar 

  24. Richards AL, Jones L, Moskvina V, Kirov G, Gejman PV, Levinson DF et al. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Mol Psychiatry 2011 (e-pub ahead of print).

  25. Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 2010; 6: e1000952.

    Article  Google Scholar 

  26. Sasaki J, Kofuji S, Itoh R, Momiyama T, Takayama K, Murakami H et al. The PtdIns(3,4)P phosphatase INPP4A is a suppressor of excitotoxic neuronal death. Nature 2010; 465: 497–501.

    Article  CAS  Google Scholar 

  27. Rao JS, Harry GJ, Rapoport SI, Kim HW . Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 2010; 15: 384–392.

    Article  CAS  Google Scholar 

  28. Berridge MJ . The Albert Lasker medical awards. Inositol trisphosphate, calcium, lithium, and cell signaling. JAMA 1989; 262: 1834–1841.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by 5R01MH080425 (to CL), PAAR (Pharmacogenetics of Anti-cancer Agents Research; U01 GM61393), ENDGAMe (ENhancing Development of Genome-wide Association Methods) initiative (U01 HL084715), and the Genotype-Tissue Expression project (GTeX) (R01 MH090937) (to NJC).

Author Contributions

ERG and CL conceived and designed the study. ERG and JAB performed statistical analyses. ERG and NJC provided analysis tools. ERG and CL wrote the manuscript. CL coordinated and supervised the study. LC, CZ, DZ, ESG, JRK, TAG, CMN, RM, PDS, NJS, ENS, CSB, JIN, Jr HJE, TF, DLK, WAS, WC, JR, WB, FJM, TGS, WHB, JBP, PPZ, PBM, MGM, SZ, PZ, DWC, SS, TBB, CL participated in patient diagnosis and sample collection. All authors edited and approved the manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Chicago, Chicago, IL, USA

    E R Gamazon & N J Cox

  2. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    J A Badner & E S Gershon

  3. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    L Cheng, C Zhang, C Chen & C Liu

  4. School of Medicine, University of Zhejiang, Hanzhou, Zhejiang, China

    D Zhang

  5. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    J R Kelsoe, T A Greenwood, C M Nievergelt, R McKinney & P D Shilling

  6. Scripps Genomic Medicine and Scripps Translational Science Institute, La Jolla, CA, USA

    N J Schork, E N Smith & C S Bloss

  7. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    J I Nurnberger & D L Koller

  8. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    H J Edenberg & T Foroud

  9. Department of Psychiatry, Rush University, Chicago, IL, USA

    W A Scheftner

  10. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    W Coryell

  11. Division of Biostatistics, Washington University, St Louis, MO, USA

    J Rice

  12. Department of Psychiatry, Howard University, Washington, DC, USA

    W B Lawson, E A Nwulia & M Hipolito

  13. Department of Psychiatry, University of California, San Francisco, CA, USA

    W Byerley

  14. US Department of Health and Human Services, Genetic Basis of Mood and Anxiety Disorders Unit, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    F J McMahon & T G Schulze

  15. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

    T G Schulze

  16. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    W H Berrettini

  17. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J B Potash, P P Zandi & P B Mahon

  18. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    M G McInnis, S Zöllner & P Zhang

  19. Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA

    D W Craig & S Szelinger

  20. Department of Psychiatry, Portland VA Medical Center, Portland, OR, USA

    T B Barrett

Authors
  1. E R Gamazon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J A Badner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N J Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E S Gershon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J R Kelsoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T A Greenwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C M Nievergelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R McKinney
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P D Shilling
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. N J Schork
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. E N Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. C S Bloss
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. J I Nurnberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. H J Edenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. T Foroud
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. D L Koller
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. W A Scheftner
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. W Coryell
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. J Rice
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. W B Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. E A Nwulia
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. M Hipolito
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. W Byerley
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. F J McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. T G Schulze
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. W H Berrettini
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. J B Potash
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. P P Zandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. P B Mahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. M G McInnis
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. S Zöllner
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. P Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. D W Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. S Szelinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. T B Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. C Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Liu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gamazon, E., Badner, J., Cheng, L. et al. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry 18, 340–346 (2013). https://doi.org/10.1038/mp.2011.174

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2011.174

Keywords

This article is cited by

Search

Advanced search

Quick links