CoChat
Sign Up
Cited by 452Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenomics and Chromatin Dynamics

An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome

Open access
Ng, Bernard, White, Charles C, Klein, Hans-Ulrich, Sieberts, Solveig K, McCabe, Cristin, Patrick, Ellis, Xu, Jishu, Yu, Lei +4 more·2017·Nature Neuroscience
DOI 10.1038/nn.4632PMC PMC5785926
Open this paper in CoChat — free account

Abstract

We report a multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adults who have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also reanalyze published genome wide association studies using an xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based expression eQTL resource.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nn.4632

Cites

17 of 17 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • rs10191329 displayed a methylation quantitative trait locus effect in the promoter region of DYSF in the dorsolateral prefrontal cerebral cortex.

    “This variant also displayed a methylation quantitative trait locus (QTL) effect in the promoter region of DYSF (ENSR00001922663) in the dorsolateral prefrontal cerebral cortex21 (Supplementary Table 13).”

    From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [21]

    The Introduction and Results > xQTL Discovery describe methylation QTL analyses in dorsolateral prefrontal cortex tissue. However, searches for rs10191329, DYSF, and ENSR00001922663 found no passage in our copy identifying the claimed variant–promoter methylation effect. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 38

  1. [1]Welter D The NHGRI GWAS Catalog, a curated resource of SNP-trait associations Nucleic Acids Res 42 D1001 1006 10.1093/nar/gkt1229 2014 24316577 PMC3965119 · DOI · Paper page
  2. [2]Alexander RP Fang G Rozowsky J Snyder M Gerstein MB Annotating non-coding regions of the genome Nat Rev Genet 11 559 571 10.1038/nrg2814 2010 20628352 · DOI · Paper page
  3. [3]Goldstein DB Common genetic variation and human traits New England Journal of Medicine 360 1696 2009 19369660
  4. [4]Pickrell JK Understanding mechanisms underlying human gene expression variation with RNA sequencing Nature 464 768 772 10.1038/nature08872 2010 20220758 PMC3089435 · DOI · Paper page
  5. [5]Lappalainen T Transcriptome and genome sequencing uncovers functional variation in humans Nature 501 506 511 10.1038/nature12531 2013 24037378 PMC3918453 · DOI · Paper page
  6. [6]Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans Science 348 648 660 10.1126/science.1262110 2015 25954001 PMC4547484 · DOI · Paper page
  7. [8]Hannon E Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci Nat Neurosci 19 48 54 10.1038/nn.4182 2016 26619357 PMC4714325 · DOI
  8. [9]McVicker G Identification of genetic variants that affect histone modifications in human cells Science 342 747 749 10.1126/science.1242429 2013 24136359 PMC3947669 · DOI
  9. [10]Nicolae DL Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS PLoS Genet 6 e1000888 10.1371/journal.pgen.1000888 2010 20369019 PMC2848547 · DOI · Paper page
  10. [11]Gamazon ER A gene-based association method for mapping traits using reference transcriptome data Nat Genet 47 1091 1098 10.1038/ng.3367 2015 26258848 PMC4552594 · DOI
  11. [12]Ionita-Laza I McCallum K Xu B Buxbaum JD A spectral approach integrating functional genomic annotations for coding and noncoding variants Nat Genet 48 214 220 10.1038/ng.3477 2016 26727659 PMC4731313 · DOI
  12. [13]Zhu Z Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets Nat Genet 48 481 487 10.1038/ng.3538 2016 27019110 · DOI · Paper page
  13. [14]Bennett DA Schneider JA Arvanitakis Z Wilson RS Overview and findings from the religious orders study Curr Alzheimer Res 9 628 645 2012 22471860 PMC3409291
  14. [15]Bennett DA Overview and findings from the rush Memory and Aging Project Curr Alzheimer Res 9 646 663 2012 22471867 PMC3439198
  15. [16]De Jager PL A genome-wide scan for common variants affecting the rate of age-related cognitive decline Neurobiol Aging 33 1017 e1011 1015 10.1016/j.neurobiolaging.2011.09.033 2012 PMC3307898 22054870 · DOI
  16. [20]Stegle O Parts L Durbin R Winn J A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies PLoS Comput Biol 6 e1000770 2010 20463871 PMC2865505
  17. [22]Do C Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation Am J Hum Genet 98 934 955 10.1016/j.ajhg.2016.03.027 2016 27153397 PMC4863666 · DOI
  18. [23]Fromer M Gene expression elucidates functional impact of polygenic risk for schizophrenia Nat Neurosci 19 1442 1453 10.1038/nn.4399 2016 27668389 PMC5083142 · DOI · Paper page
  19. [25]Storey JD Tibshirani R Statistical significance for genomewide studies Proc Natl Acad Sci U S A 100 9440 9445 10.1073/pnas.1530509100 2003 12883005 PMC170937 · DOI · Paper page
  20. [26]Battle A Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals Genome research 24 14 24 2014 24092820 PMC3875855
  21. [28]The Genotype-Tissue Expression (GTEx) project Nat Genet 45 580 585 10.1038/ng.2653 2013 23715323 PMC4010069 · DOI · Paper page
  22. [30]Pontillo A Catamo E Arosio B Mari D Crovella S NALP1/NLRP1 genetic variants are associated with Alzheimer disease Alzheimer Dis Assoc Disord 26 277 281 10.1097/WAD.0b013e318231a8ac 2012 21946017 · DOI
  23. [31]Ernst J Kellis M ChromHMM: automating chromatin-state discovery and characterization Nat Methods 9 215 216 10.1038/nmeth.1906 2012 22373907 PMC3577932 · DOI
  24. [32]Gaffney DJ Dissecting the regulatory architecture of gene expression QTLs Genome Biol 13 R7 10.1186/gb-2012-13-1-r7 2012 22293038 PMC3334587 · DOI
  25. [33]Johnson AD Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues Pharmacogenet Genomics 18 781 791 10.1097/FPC.0b013e3283050107 2008 18698231 PMC2779843 · DOI
  26. [34]Nishida H Histone H3 acetylated at lysine 9 in promoter is associated with low nucleosome density in the vicinity of transcription start site in human cell Chromosome Res 14 203 211 10.1007/s10577-006-1036-7 2006 16544193 · DOI
  27. [35]Millstein J Zhang B Zhu J Schadt EE Disentangling molecular relationships with a causal inference test BMC Genet 10 23 10.1186/1471-2156-10-23 2009 19473544 PMC3224661 · DOI
  28. [38]Gaulton KJ Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci Nat Genet 47 1415 1425 10.1038/ng.3437 2015 26551672 PMC4666734 · DOI
  29. [39]Finucane HK Partitioning heritability by functional annotation using genome-wide association summary statistics Nat Genet 47 1228 1235 10.1038/ng.3404 2015 26414678 PMC4626285 · DOI · Paper page
  30. [41]Del Villar K Miller CA Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer’s disease brain and hippocampal neurons Proc Natl Acad Sci U S A 101 4210 4215 10.1073/pnas.0307349101 2004 15007167 PMC384720 · DOI
  31. [43]Westra HJ Cell Specific eQTL Analysis without Sorting Cells PLoS Genet 11 e1005223 10.1371/journal.pgen.1005223 2015 25955312 PMC4425538 · DOI
  32. [44]Roeder K Devlin B Wasserman L Improving power in genome-wide association studies: weights tip the scale Genet Epidemiol 31 741 747 10.1002/gepi.20237 2007 17549760 · DOI
  33. [45]Chang CC Second-generation PLINK: rising to the challenge of larger and richer datasets Gigascience 4 7 10.1186/s13742-015-0047-8 2015 25722852 PMC4342193 · DOI · Paper page
  34. [46]Shi Y Common variants on 8p12 and 1q24.2 confer risk of schizophrenia Nat Genet 43 1224 1227 10.1038/ng.980 2011 22037555 PMC3773910 · DOI
  35. [47]Huang L Hu F Zeng X Gan L Luo XJ Further evidence for the association between the LSM1 gene and schizophrenia Schizophr Res 150 588 589 10.1016/j.schres.2013.07.023 2013 24035562 · DOI
  36. [48]Iossifov I The contribution of de novo coding mutations to autism spectrum disorder Nature 515 216 221 10.1038/nature13908 2014 25363768 PMC4313871 · DOI · Paper page
  37. [49]Bestman JE Cline HT The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo Proc Natl Acad Sci U S A 105 20494 20499 10.1073/pnas.0806296105 2008 19074264 PMC2629308 · DOI
  38. [50]Ruderfer DM Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia Mol Psychiatry 19 1017 1024 10.1038/mp.2013.138 2014 24280982 PMC4033708 · DOI · Paper page

Cited by

Sorted by citations

Authors
Ng, B., White, C. C., Klein, H.-U., Sieberts, S. K., McCabe, C., Patrick, E., Xu, J., Yu, L., Gaiteri, C., Bennett, D. A., Mostafavi, S., & De Jager, P. L.
Affiliations
  • University of British Columbia (CA)
  • Broad Institute (US)
  • Sage Bionetworks (US)
  • Rush University Medical Center (US)
  • Canadian Institute for Advanced Research (CA)
Corresponding author
Mostafavi, Sara
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2017-09-04
Volume
20
Issue
10
Pages
1418-1426
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4632
PMC
PMC5785926
OpenAlex
W2949785910
Cited by
452
References
17
Citations by year
2026: 30 · 2025: 47 · 2024: 54 · 2023: 60 · 2022: 65 · 2021: 67 · 2020: 55 · 2019: 41 · 2018: 26 · 2017: 3 · 2016: 1
FWCI
22.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R01AG017917, R01AG036836, U01AG046152, R01AG015819, P30AG010161, RC2AG036547, RF1AG015819, RF1AG036042)
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
expression quantitative trait loci, DNA methylation, H3K9ac, histone acetylation, dorsolateral prefrontal cortex, brain transcriptome, epigenetic mediation, older adults
MeSH terms
Bipolar Disorder, Brain, Humans, Schizophrenia, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Epigenesis, Genetic, Genome-Wide Association Study, Epigenomics, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review