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.

  • Article
  • Published:

Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders

Molecular Psychiatry volume 26, pages 2082–2088 (2021)Cite this article

Subjects

Abstract

The majority of common risk alleles identified for neuropsychiatric disorders reside in noncoding regions of the genome and are therefore likely to impact gene regulation. However, the genes that are primarily affected and the nature and developmental timing of these effects remain unclear. Given the hypothesized role for early neurodevelopmental processes in these conditions, we here define genetic predictors of gene expression in the human fetal brain with which we perform transcriptome-wide association studies (TWASs) of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia. We identify prenatal cis-regulatory effects on 63 genes and 166 individual transcripts associated with genetic risk for these conditions. We observe pleiotropic effects of expression predictors for a number of genes and transcripts, including those of decreased DDHD2 expression in association with risk for schizophrenia and bipolar disorder, increased expression of a ST3GAL3 transcript with risk for schizophrenia and ADHD, and increased expression of an XPNPEP3 transcript with risk for schizophrenia, bipolar disorder, and major depression. For the protocadherin alpha cluster genes PCDHA7 and PCDHA8, we find that predictors of low expression are associated with risk for major depressive disorder while those of higher expression are associated with risk for schizophrenia. Our findings support a role for altered gene regulation in the prenatal brain in susceptibility to various neuropsychiatric disorders and prioritize potential risk genes for further neurobiological investigation.

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

Fig. 1: TWAS Z-scores across all five tested neuropsychiatric disorders for predictors of cis-heritable gene expression that are significantly associated with at least two conditions (gene-level analysis).
Fig. 2: TWAS Z-scores across all five tested neuropsychiatric disorders for predictors of cis-heritable gene expression that are significantly associated with at least two conditions (transcript-level analysis).

Similar content being viewed by others

Data availability

The SNP weights for predictors of fetal brain gene- and transcript-level expression that were generated and analyzed in the current study are available in a Figshare repository (https://doi.org/10.6084/m9.figshare.11637036). Individual RNA-Seq FASTQ files are available through the European Genome-phenome Archive (https://ega-archive.org) under study accession EGAS00001003214.

References

  1. Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.

    Article  Google Scholar 

  2. Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.

    Article  CAS  Google Scholar 

  3. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019;51:63–75.

    Article  CAS  Google Scholar 

  4. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44.

    Article  CAS  Google Scholar 

  5. Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51:793–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    Article  CAS  Google Scholar 

  7. Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, et al. Nat Genet. 2015;47:1091–8.

    Article  CAS  Google Scholar 

  8. Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx BW, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48:245–52.

    Article  CAS  Google Scholar 

  9. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

    Article  CAS  Google Scholar 

  10. O’Donnell KJ, Meaney MJ. Fetal origins of mental health: the developmental origins of health and disease hypothesis. Am J Psychiatry. 2017;174:319–28.

    Article  Google Scholar 

  11. de la Torre-Ubieta L, Stein JL, Won H, Opland CK, Liang D, Lu D, et al. The dynamic landscape of open chromatin during human cortical neurogenesis. Cell. 2018;172:289–304.

    Article  Google Scholar 

  12. Schork AJ, Won H, Appadurai V, Nudel R, Gandal M, Delaneau O, et al. A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nat Neurosci. 2019;22:353–61.

    Article  CAS  Google Scholar 

  13. O’Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19:194.

    Article  Google Scholar 

  14. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127. pii

    Article  CAS  Google Scholar 

  15. Duarte RRR, Troakes C, Nolan M, Srivastava DP, Murray RM, Bray NJ. Genome-wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis-regulation of BORCS7, AS3MT, and NT5C2 in the human brain. Am J Med Genet B Neuropsychiatr Genet. 2016;171:806–14.

    Article  CAS  Google Scholar 

  16. Walker RL, Ramaswami G, Hartl C, Mancuso N, Gandal MJ, de la Torre-Ubieta L, et al. Genetic control of expression and splicing in developing human brain informs disease mechanisms. Cell. 2019;179:750–71.

    Article  CAS  Google Scholar 

  17. Takata A, Matsumoto N, Kato T. Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci. Nat Commun. 2017;8:14519.

    Article  CAS  Google Scholar 

  18. Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018;50:538–48.

    Article  CAS  Google Scholar 

  19. Veit G, Kobbe B, Keene DR, Paulsson M, Koch M, Wagener R. Collagen XXVIII, a novel von Willebrand factor A domain-containing protein with many imperfections in the collagenous domain. J Biol Chem. 2006;281:3494–504.

    Article  CAS  Google Scholar 

  20. Liao C, Laporte AD, Spiegelman D, Akçimen F, Joober R, Dion PA, et al. Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes. Nat Commun. 2019;10:4450.

    Article  Google Scholar 

  21. Hu H, Eggers K, Chen W, Garshasbi M, Motazacker MM, Wrogemann K, et al. ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet. 2011;89:407–14.

    Article  CAS  Google Scholar 

  22. Walton E, Pingault JB, Cecil CA, Gaunt TR, Relton CL, Mill J, et al. Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry. 2017;22:250–6.

    Article  CAS  Google Scholar 

  23. Pain O, Pocklington AJ, Holmans PA, Bray NJ, O’Brien HE, Hall LS, et al. Novel insight into the etiology of autism spectrum disorder gained by integrating expression data with genome-wide association statistics. Biol Psychiatry. 2019;86:265–73.

    Article  CAS  Google Scholar 

  24. Huckins LM, Dobbyn A, McFadden W, Wang W, Ruderfer DM, Hoffman G, et al. Transcriptomic imputation of bipolar disorder and bipolar subtypes reveals 29 novel associated genes. Preprint at: https://www.biorxiv.org/content/10.1101/222786v1.

  25. Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, et al. Clinical delineation of the PACS1-related syndrome-Report on 19 patients. Am J Med Genet A. 2016;170:670–5.

    Article  CAS  Google Scholar 

  26. Thu CA, Chen WV, Rubinstein R, Chevee M, Wolcott HN, Felsovalyi KO, et al. Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins. Cell. 2014;158:1045–59.

    Article  CAS  Google Scholar 

  27. Inloes JM, Hsu KL, Dix MM, Viader A, Masuda K, Takei T, et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc Natl Acad Sci USA. 2014;111:14924–9.

    Article  CAS  Google Scholar 

  28. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179:1469–82.

    Article  Google Scholar 

  29. Bray NJ, Hill MJ. Translating genetic risk loci into molecular risk mechanisms for schizophrenia. Schizophr Bull. 2016;42:5–8.

    PubMed  Google Scholar 

  30. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br Med J. 1987;295:681–2.

    Article  CAS  Google Scholar 

  31. Brainstorm Consortium. Analysis of shared heritability in common disorders of the brain. Science. 2018;360:eaap8757.

    Article  Google Scholar 

  32. Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, et al. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci. 2019;22:229–42.

    Article  Google Scholar 

  33. Vadodaria KC, Ji Y, Skime M, Paquola AC, Nelson T, Hall-Flavin D, et al. Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry. 2019;24:808–18.

    Article  Google Scholar 

  34. Nord AS, Blow MJ, Attanasio C, Akiyama JA, Holt A, Hosseini R, et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell. 2013;155:1521–31.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Medical Research Council (MRC) (U.K.) project grants to NJB (MR/L010674/1, MR/L010674/2 and MR/T002379/1) and an MRC Centre grant to MJO (MR/L010305/1). The human fetal material was provided by the Joint MRC/Wellcome Trust (grant #099175/Z/12/Z) Human Developmental Biology Resource (www.hdbr.org). We thank the research participants and employees of 23andMe for their contribution to the major depressive disorder GWAS data used in this study.

Author information

Authors and Affiliations

  1. MRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, UK

    Lynsey S. Hall, Oliver Pain, Heath E. O’Brien, Richard Anney, James T. R. Walters, Michael J. Owen, Michael C. O’Donovan & Nicholas J. Bray

  2. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Oliver Pain

Authors
  1. Lynsey S. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Pain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heath E. O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Anney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James T. R. Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael C. O’Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nicholas J. Bray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas J. Bray.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hall, L.S., Pain, O., O’Brien, H.E. et al. Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders. Mol Psychiatry 26, 2082–2088 (2021). https://doi.org/10.1038/s41380-020-0743-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0743-3

This article is cited by

Search

Advanced search

Quick links