Abstract
It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
206,07 € per year
only 17,17 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Hovatta, I. et al. DNA variation and brain-region specific expression profiles show different relationships between inbred mouse strains: implications for eQTL mapping studies. Genome Biol. 8, R25 (2007).
Hovatta, I. et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438, 662–666 (2005).
McClurg, P. et al. Genomewide association analysis in diverse inbred mice: power and population structure. Genetics 176, 675–683 (2007).
Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).
Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).
Cheung, V.G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).
Stranger, B.E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005).
Gilbert, J.M., Brown, B.A., Strocchi, P., Bird, E.D. & Marotta, C.A. The preparation of biologically active messenger RNA from human postmortem brain tissue. J. Neurochem. 36, 976–984 (1981).
Lambert, J.C. et al. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Hum. Mol. Genet. 6, 2151–2154 (1997).
Bray, N.J. et al. Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes. Hum. Mol. Genet. 13, 2885–2892 (2004).
Myers, A.J. et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol. Dis. 25, 561–570 (2007).
Coon, K.D. et al. A high density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J. Clin. Psychiatry 68, 613–618 (2007).
Workman, C. et al. A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol. 3, research0048 (2002).
Schadt, E.E., Li, C., Ellis, B. & Wong, W.H. Feature extraction and normalization algorithms for high-density oligonucleotide gene expression array data. J. Cell. Biochem. Suppl. (Suppl. 37) 120–125 (2001).
Tseng, G.C., Oh, M.K., Rohlin, L., Liao, J.C. & Wong, W.H. Issues in cDNA microarray analysis: quality filtering, channel normalization, models of variations and assessment of gene effects. Nucleic Acids Res. 29, 2549–2557 (2001).
Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).
Falush, D., Stephens, M. & Pritchard, J.K. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Tukey, J.W. Exploratory Data Analysis Section 2C (Addison-Wesley, Reading, Massachusetts, 1977).
Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Acknowledgements
We thank the individuals involved in this study and their families. Many data and biomaterials were collected from several sites funded by the National Institute on Aging (NIA) and National Alzheimer's Coordinating Center (NACC, grant #U01 AG016976). A.J. Myers (University of Miami, Department of Psychiatry) and J.A. Hardy (Reta Lila Weston Institute, University College London) collected and prepared the series. We thank M. Morrison-Bogorad, T. Phelps and W. Kukull for helping to coordinate this collection. The directors, pathologists and technicians involved include: R. Seemann (NIA); J.C. Troncoso and O. Pletnikova (Johns Hopkins Alzheimer's Disease Research Center, NIA grant AG05146); H. Vinters and J. Pomakian (University of California Los Angeles, NIA grant P50 AG16570); C. Hulette and J.F. Ervin (The Kathleen Price Bryan Brain Bank, Duke University Medical Center, NIA grant AG05128, National Institute of Neurological Disorders and Stroke grant NS39764, National Institute of Mental Health MH60451, also funded by Glaxo Smith Kline); D. Horoupian and A. Salehi (Stanford University); J.P. Vonsattel and K. Mancevska (New York Brain Bank, Taub Institute, Columbia University); E.T. Hedley-Whyte and K. Fitch (Massachusetts General Hospital); R. Albin, L. Bain and E. Gombosi (University of Michigan, National Institutes of Health (NIH) grant P50-AG08671); W. Markesbery and S. Anderson (University of Kentucky, NIH grant AG05144); D.W. Dickson and N. Thomas (Mayo Clinic, Jacksonville); C.A. Miller, J. Tang and D. Diaz (University of Southern California); D. McKeel, J.C. Morris, E. Johnson Jr., V. Buckles and D. Carter (Washington University, St. Louis, Alzheimer's Disease Research Center (NIH grant P50AG05681); T. Montine and A. Schantz (University of Washington, Seattle, NIH grant P50 AG05136); J.Q. Trojanowski, V.M. Lee, V. Van Deerlin and T. Schuck (University of Pennsylvania School of Medicine, Alzheimer's Disease Research Center); A.C. McKee and C. Kubilus (Boston University Alzheimer's Disease Research Center, NIH grant P30-AG13846); J. Rogers, T.G. Beach and L.I. Sue (Sun Health Research Institute, Arizona, NIA grant P30 AG19610); B.H. Wainer and M. Gearing (Emory University); C.L. White III, R. Rosenberg, M. Howell and J. Reisch (University of Texas Southwestern Medical School); W. Ellis and M.A. Jarvis (University of California, Davis); D.A. Bennett, J.A. Schneider, K. Skish and W.T. Longman (Rush University Medical Center, Rush Alzheimer's Disease Center, NIH grant AG10161); and D.C. Mash, M.J. Basile and M. Tanaka (University of Miami/NPF Brain Endowment Bank). These studies were supported by Kronos Sciences Laboratory, the Verum Foundation, the Bisgrove charitable donation, the NIH Neuroscience Blueprint (U24NS051872), the ENDGAME Consortium (UO1HL084744) and the state of Arizona. We also thank E.B. Suh and J. Lowey at TGen for the use of the ASU-TGen cluster-based supercomputer. A.J.M. would like to thank the Johnnie B. Byrd Institute for support. None of the sponsors were involved in the design or conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Author information
Authors and Affiliations
Contributions
A.J.M. conceived the experiment, supervised and performed the RNA screen and wrote the final manuscript. J.R.G. helped to refine the experiment and performed the final data analysis as well as helped to edit the manuscript. J.A.W. performed and supervised the DNA screen, carried out the permutation analysis and helped to edit the manuscript. K.R., A.Z., L.M., M.K., D.L., L.B. and P.N. helped to perform the RNA screen and APOE genotyping. V.L.Z., K.J., M.J.H., D.H.-L. and K.D.C. helped to perform the DNA screen. D.W.C. and J.V.P. performed initial analyses on the DNA screen. P.H. served as a statistical consultant for the final data analysis and helped edit the manuscript. C.B.H. helped to fund the study. E.M.R. and D.S. supervised the DNA portion of the screen as well as helped to fund the study. J.H. helped to conceive the experiment and wrote the first draft of the manuscript.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1 and 2 (PDF 328 kb)
Information
Supplementary Tables 1 (XLS 13 kb)
Supplementary Information
Supplementary Tables 2 (XLS 177 kb)
Supplementary Information
Supplementary Tables 3 (XLS 37 kb)
SupplementaryInformation
Supplementary Tables 4 (XLS 156 kb)
Rights and permissions
About this article
Cite this article
Myers, A., Gibbs, J., Webster, J. et al. A survey of genetic human cortical gene expression. Nat Genet 39, 1494–1499 (2007). https://doi.org/10.1038/ng.2007.16
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.2007.16
