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Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions

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Sieberts, Solveig K., Perumal, Thanneer M., Carrasquillo, Minerva M., Allen, Mariet, Reddy, Joseph S., Hoffman, Gabriel E., Dang, Kristen K., Calley, John +180 more·2020·Scientific Data
DOI 10.1038/s41597-020-00642-8PMC PMC7550587

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Abstract

The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis- eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).

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  • 53 of the cis-pQTLs identified in this study showed previous evidence of association with gene expression in brain tissues.

    “When comparing with the eQTL meta‐analysis study, 53 of the cis‐pQTLs identified in the current study showed previous evidence of association with gene expression in brain tissues.”

    From The genetic regulation of protein expression in cerebrospinal fluid (2023) · cites this paper as Sieberts et al, 2020

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Authors
Sieberts, S. K., Perumal, T. M., Carrasquillo, M. M., Allen, M., Reddy, J. S., Hoffman, G. E., Dang, K. K., Calley, J., Ebert, P. J., Eddy, J., Wang, X., Greenwood, A. K., Mostafavi, S., The CommonMind Consortium (CMC), Akbarian, S., Bendl, J., Breen, M. S., Brennand, K., Brown, L., Browne, A., Buxbaum, J. D., Charney, A., Chess, A., Couto, L., Crawford, G., Devillers, O., Devlin, B., Dobbyn, A., Domenici, E., Filosi, M., Flatow, E., Francoeur, N., Fullard, J., Gil, S. E., Girdhar, K., Gulyás-Kovács, A., Gur, R., Hahn, C.-G., Haroutunian, V., Hauberg, M. E., Huckins, L., Jacobov, R., Jiang, Y., Johnson, J. S., Kassim, B., Kim, Y., Klei, L., Kramer, R., Lauria, M., Lehner, T., Lewis, D. A., Lipska, B. K., Montgomery, K., Park, R., Rosenbluh, C., Roussos, P., Ruderfer, D. M., Senthil, G., Shah, H. R., Sloofman, L., Song, L., Stahl, E., Sullivan, P., Visintainer, R., Wang, J., Wang, Y.-C., Wiseman, J., Xia, E., Zhang, W., Zharovsky, E., The AMP-AD Consortium, Addis, L., Addo, S. N., Airey, D. C., Arnold, M., Bennett, D. A., Bi, Y., Biber, K., Blach, C., Bradhsaw, E., Brennan, P., Canet-Aviles, R., Cao, S., Cavalla, A., Chae, Y., Chen, W. W., Cheng, J., Collier, D. A., Dage, J. L., Dammer, E. B., Davis, J. W., Davis, J., Drake, D., Duong, D., Eastwood, B. J., Ehrlich, M., Ellingson, B., Engelmann, B. W., Esmaeelinieh, S., Felsky, D., Funk, C., Gaiteri, C., Gandy, S., Gao, F., Gileadi, O., Golde, T., Grosskurth, S. E., Gupta, R. R., Gutteridge, A. X., Haroutunian, V., Hooli, B., Humphryes-Kirilov, N., Iijima, K., James, C., Jung, P. M., Kaddurah-Daouk, R., Kastenmuller, G., Klein, H.-U., Kummer, M., Lacor, P. N., Lah, J., Laing, E., Levey, A., Li, Y., Lipsky, S., Liu, Y., Liu, J., Liu, Z., Louie, G., Lu, T., Ma, Y., Matsuoka, Y. Y., Menon, V., Miller, B., Misko, T. P., Mollon, J. E., Montgomery, K., Mukherjee, S., Noggle, S., Pao, P.-C., Pearce, T. Y., Pearson, N., Penny, M., Petyuk, V. A., Price, N., Quarless, D. X., Ravikumar, B., Ried, J. S., Ruble, C. L. A., Runz, H., Saykin, A. J., Schadt, E., Scherschel, J. E., Seyfried, N., Shulman, J. M., Snyder, P., Soares, H., Srivastava, G. P., Stockmann, H., Taga, M., Tasaki, S., Tenenbaum, J., Tsai, L.-H., Vasanthakumar, A., Wachter, A., Wang, Y., Wang, H., Wang, M., Whelan, C. D., White, C., Woo, K. H., Wren, P., Wu, J. W., Xi, H. S., Yankner, B. A., Younkin, S. G., Yu, L., Zavodszky, M., Zhang, W., Zhang, G., Zhang, B., Zhu, J., Omberg, L., Peters, M. A., Logsdon, B. A., De Jager, P. L., Ertekin-Taner, N., & Mangravite, L. M.
Affiliations
  • Sage Bionetworks (US)
  • Mayo Clinic in Florida (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Eli Lilly (United States) (US)
  • Canadian Institute for Advanced Research (CA)
  • Duke University (US)
  • University of Pittsburgh (US)
  • University of Trento (IT)
  • University of Pennsylvania (US)
  • Aarhus University (DK)
  • National Institutes of Health (US)
  • National Institute of Mental Health (US)
  • Vanderbilt University (US)
  • University of North Carolina at Chapel Hill (US)
  • AbbVie (United States) (US)
  • Helmholtz Munich (DE)
  • Rush University Medical Center (US)
  • Columbia University Irving Medical Center (US)
  • University of Oxford (GB)
  • Foundation for the National Institutes of Health (US)
  • Biogen (United States) (US)
  • Emory University (US)
  • Harvard University (US)
  • Institute for Systems Biology (US)
  • Massachusetts Institute of Technology (US)
  • University of Florida (US)
  • GlaxoSmithKline (United Kingdom) (GB)
  • National Center for Geriatrics and Gerontology (JP)
  • Baylor College of Medicine (US)
  • New York Stem Cell Foundation (US)
  • Pacific Northwest National Laboratory (US)
  • Indiana University School of Medicine (US)
  • Broad Institute (US)
Corresponding author
  • Sieberts, Solveig K.
  • Mangravite, Lara M.
ORCID
Venue
Scientific Data
Publisher
Springer Science and Business Media LLC
Published
2020-10-12
Volume
7
Issue
1
Pages
340-340
ISSN
2052-4463 (ISSN-L)
DOI
10.1038/s41597-020-00642-8
PMC
PMC7550587
OpenAlex
W3092045521
Cited by
318
References
12
Citations by year
2026: 8 · 2025: 15 · 2024: 16 · 2023: 16 · 2022: 22 · 2021: 202 · 2020: 37 · 2019: 1
Type
data paper
Language
en
Open access
Licence
Locations
  • Scientific Data (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • Site cant be reached (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (U24 NS072026, 05-901, 211002, P30 AG19610)
  • Mayo Clinic (05-901, U24 NS072026, U01 AG046139, P30 AG19610, P50 AG016574, R01 AG032990, U01 AG006786, RF1 AG051504, R01 NS080820, 211002)
  • Illinois Department of Public Health (P30AG10161, R01AG15819, R01AG17917, R01AG30146)
  • University of Pennsylvania
  • F. Hoffmann-La Roche (U01MH103392, P50MH084053S1, R01MH097276, R01MH093725, R37MH057881, MH06692, P50M096891, AG02219, RO1-MH-075916, R01MH085542, AG05138, HHSN271201300031C, P50MH066392, P50MH080405)
  • Mayo Foundation for Medical Education and Research (U24 NS072026, AG016574)
  • Arizona Department of Health Services (HHSN271201300031C, P30 AG19610, P50 AG016574, U24 NS072026, 05-901, 211002, Contract 211002, R01 AG032990)
  • University of Pittsburgh
  • CurePSP
  • Rush University (P30AG10161, R01 AG15819, R01AG30146)
  • Translational Genomics Research Institute
  • Università degli Studi di Trento
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, Contracts 4001, 0011, 05‐901 and 1001, U24 NS072026, 4001, 0011, 05-901, and 1001, 211002)
  • National Institutes of Health (MH06692, 05-901, P50M096891, 5r01mh080405-05, 211002, HHSN271201300031C, AG016574, P50MH080405, AG046139, AG05138, AG19610, AG017216, AG02219, P50MH084053S1, AG003949, AG025711)
  • National Institute on Aging (211002, R01AG017917, U01-AG006576, R01AG030146, RF1AG051504, AG-02219, R01 AG, R01 AG003949, AG046139, U01AG046170, R01AG018023, AG016574, AG051504, R01AG036836, AG 05138, AG-19610, P50AG005138, U01AG046152, U01AG006786, P01AG003949, AG-006786, R01-AG025711, R01AG015819, F31AG051381, P30AG010161, T32AG049688, U01AG032984, RF1AG057443, R01AG046174, P50AG025711, AG025711, R01AG032990, R03AG022193, P30AG019610, U01AG046161, 05-901, P01AG017216, U01AG046139, R01AG061796, R01AG046171, AG017216, P01AG002219, AG003949, AG061796, U24AG061340, P30AG066514, P30AG062677, R01-AG017216, P50AG016574)
  • National Institute of Mental Health (P50MH084053, R01 MH‐080405, P50MH096891, HHSN271201300031C, 05-901, R01MH093725, P50MH066392, R01MH109677, 211002, R03MH066923, R01MH075916, R01MH085542, R37MH057881, R01MH109897, R01MH097276, U01MH103392, P50MH084051, R01MH110921)
  • National Institute on Drug Abuse (HHSN271201300031C)
  • National Institute of Neurological Disorders and Stroke (R01NS080820, NS072026, 211002, NS080820, U24NS072026, 05-901, U24 NS072026 National Brain)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
cis-eQTL, expression quantitative trait loci, cerebral cortex, cerebellum, postmortem brain, colocalization analysis, schizophrenia
MeSH terms
Cerebellar Cortex, Cerebral Cortex, Humans, Schizophrenia, Meta-Analysis as Topic, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study, RNA, Long Noncoding, Datasets as Topic

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