Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population

Article metrics


We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06–1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13–1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07–1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, β = –0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, β = –0.044) and verbal working memory (p = 0.0062, β = −0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. 1.

    Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006;109:366–98.

  2. 2.

    Davis RL. Physiology and biochemistry of Drosophila learning mutants. Physiol Rev. 1996;76:299–317.

  3. 3.

    Davis RL, Cherry J, Dauwalder B, Han PL, Skoulakis E. The cyclic AMP system and Drosophila learning. Mol Cell Biochem. 1995;149-150:271–8.

  4. 4.

    Clark SL, Souza RP, Adkins DE, Aberg K, Bukszar J, McClay JL, et al. Genome-wide association study of patient-rated and clinician-rated global impression of severity during antipsychotic treatment. Pharmacogenet Genomics. 2013;23:69–77.

  5. 5.

    Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, Hofmeister W, Anderlid BM, et al. Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. J Med Genet. 2014;51:45–54.

  6. 6.

    Lee H, Graham JM Jr., Rimoin DL, Lachman RS, Krejci P, Tompson SW, et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet. 2012;90:746–51.

  7. 7.

    Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG, et al. A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry. 2008;13:302–12.

  8. 8.

    Li YF, Cheng YF, Huang Y, Conti M, Wilson SP, O’Donnell JM, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci: the official journal of the Society for Neuroscience. 2011;31:172–83.

  9. 9.

    Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science (New York, NY). 2005;310:1187–91.

  10. 10.

    Fatemi SH, King DP, Reutiman TJ, Folsom TD, Laurence JA, Lee S, et al. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res. 2008;101:36–49.

  11. 11.

    Numata S, Ueno S, Iga J, Song H, Nakataki M, Tayoshi S, et al. Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. J Psychiatr Res. 2008;43:7–12.

  12. 12.

    Pickard BS, Thomson PA, Christoforou A, Evans KL, Morris SW, Porteous DJ, et al. The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatr Genet. 2007;17:129–33.

  13. 13.

    Pardinas 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.

  14. 14.

    Meier S, Trontti K, Als TD, Laine M, Pedersen MG, Bybjerg-Grauholm J, et al. Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort. bioRxiv. 2018.

  15. 15.

    Siuciak JA, McCarthy SA, Chapin DS, Martin AN. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology. 2008;197:115–26.

  16. 16.

    Kuroiwa M, Snyder GL, Shuto T, Fukuda A, Yanagawa Y, Benavides DR, et al. Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology (Berl). 2012;219:1065–79.

  17. 17.

    Ryan NM, Lihm J, Kramer M, McCarthy S, Morris SW, Arnau-Soler A, et al. DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders. Mol Psychiatry. 2018;23:2254–65.

  18. 18.

    Tomppo L, Hennah W, Lahermo P, Loukola A, Tuulio-Henriksson A, Suvisaari J, et al. Association between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses. Biol Psychiatry. 2009;65:1055–62.

  19. 19.

    Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet. 2003;12:3151–9.

  20. 20.

    Hennah W, Tomppo L, Hiekkalinna T, Palo OM, Kilpinen H, Ekelund J, et al. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet. 2007;16:453–62.

  21. 21.

    Ekholm JM, Pekkarinen P, Pajukanta P, Kieseppa T, Partonen T, Paunio T, et al. Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families. Mol Psychiatry. 2002;7:453–9.

  22. 22.

    Kaprio J, Koskenvuo M, Rose RJ. Population-based twin registries: illustrative applications in genetic epidemiology and behavioral genetics from the Finnish Twin Cohort Study. Acta Genet Med Gemellol (Roma). 1990;39:427–39.

  23. 23.

    Cannon TD, Kaprio J, Lonnqvist J, Huttunen M, Koskenvuo M. The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. Arch Gen Psychiatry. 1998;55:67–74.

  24. 24.

    Mantere O, Saarela M, Kieseppa T, Raij T, Mantyla T, Lindgren M, et al. Anti-neuronal anti-bodies in patients with early psychosis. Schizophr Res. 2018;192:404–7.

  25. 25.

    Aaltonen K, Naatanen P, Heikkinen M, Koivisto M, Baryshnikov I, Karpov B, et al. Differences and similarities of risk factors for suicidal ideation and attempts among patients with depressive or bipolar disorders. J Affect Disord. 2016;193:318–30.

  26. 26.

    Donner J, Pirkola S, Silander K, Kananen L, Terwilliger JD, Lonnqvist J, et al. An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biol Psychiatry. 2008;64:672–80.

  27. 27.

    van den Oord EJ, Sullivan PF. A framework for controlling false discovery rates and minimizing the amount of genotyping in the search for disease mutations. Hum Hered. 2003;56:188–99.

  28. 28.

    Sulonen AM, Ellonen P, Almusa H, Lepisto M, Eldfors S, Hannula S, et al. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol. 2011;12:R94.

  29. 29.

    Ortega-Alonso A, Ekelund J, Sarin AP, Miettunen J, Veijola J, Jarvelin MR, et al. Genome-wide association study of psychosis proneness in the Finnish Population. Schizophr Bull. 2017;43:1304–14.

  30. 30.

    Jurinke C, van den Boom D, Cantor CR, Koster H. Automated genotyping using the DNA MassArray technology. Methods in molecular biology (Clifton, NJ). 2001;170:103–16.

  31. 31.

    Gertz EM, Hiekkalinna T, Digabel SL, Audet C, Terwilliger JD, Schaffer AA. PSEUDOMARKER 2.0: efficient computation of likelihoods using NOMAD. BMC Bioinformatics. 2014;15:47.

  32. 32.

    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;81:559–75.

  33. 33.

    Wang Y, Ottman R, Rabinowitz D. A method for estimating penetrance from families sampled for linkage analysis. Biometrics. 2006;62:1081–8.

  34. 34.

    Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005;62:1205–13.

  35. 35.

    Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, et al. A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry. 2005;10:1097–103.

  36. 36.

    Paunio T, Tuulio-Henriksson A, Hiekkalinna T, Perola M, Varilo T, Partonen T, et al. Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Hum Mol Genet. 2004;13:1693–702.

  37. 37.

    Tuulio-Henriksson A, Arajarvi R, Partonen T, Haukka J, Varilo T, Schreck M, et al. Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients. Biol Psychiatry. 2003;54:623–8.

  38. 38.

    Tuulio-Henriksson A, Haukka J, Partonen T, Varilo T, Paunio T, Ekelund J, et al. Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet. 2002;114:483–90.

  39. 39.

    Wedenoja J, Loukola A, Tuulio-Henriksson A, Paunio T, Ekelund J, Silander K, et al. Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol Psychiatry. 2008;13:673–84.

  40. 40.

    Delis DKJ, Kaplan E, Ober B. California verbal learning test (CVLT). San Antonio: The Psychological Corporation; 1987.

  41. 41.

    D. W. Manual for the Wechsler adult intelligence scale-revised (WAIS-R). San Antonio, TX: The Psychological Corporation; 1981.

  42. 42.

    DW WMS-R: Wechsler memory scale-revised. San Antonio, TX: Psychological Corporation; 1987.

  43. 43.

    Golden CJ. Stroop color and word test: A Manual for Clinical and Experimental Uses. Chicago, IL: Stoelting Co. 1978.

  44. 44.

    Reitan RM. Trail Making Test: Manual for administration and scoring. Reitan Neuropsychology Laboratory. 1986.

  45. 45.

    Ukkola-Vuoti L, Torniainen-Holm M, Ortega-Alonso A, Sinha V, Tuulio-Henriksson A, Paunio T, et al. Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry. 2019;88:159–67.

  46. 46.

    Abecasis GR, Cardon LR, Cookson WO. A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000;66:279–92.

  47. 47.

    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England). 2005;21:263–5.

  48. 48.

    Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics. 1987;117:331–41.

  49. 49.

    GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.

  50. 50.

    Neale BM. Statistical genetics: gene mapping through linkage and association. Chapter 3 Introduction to biometrical genetics. New York; Abingdon England: Taylor & Francis Group; 2008. xxviii, 574 p., 4 p. of plates p.

  51. 51.

    He H, Luo C, Luo Y, Duan M, Yi Q, Biswal BB, et al. Reduction in gray matter of cerebellum in schizophrenia and its influence on static and dynamic connectivity. Hum Brain Mapp. 2018;40:517–28.

  52. 52.

    Peters H, Shao J, Scherr M, Schwerthoffer D, Zimmer C, Forstl H, et al. More consistently altered connectivity patterns for cerebellum and medial temporal lobes than for amygdala and striatum in schizophrenia. Front Hum Neurosci. 2016;10:55.

  53. 53.

    Kim DJ, Kent JS, Bolbecker AR, Sporns O, Cheng H, Newman SD, et al. Disrupted modular architecture of cerebellum in schizophrenia: a graph theoretic analysis. Schizophr Bull. 2014;40:1216–26.

  54. 54.

    O’Halloran CJ, Kinsella GJ, Storey E. The cerebellum and neuropsychological functioning: a critical review. J Clin Exp Neuropsychol. 2012;34:35–56.

  55. 55.

    Cao H, Chen OY, Chung Y, Forsyth JK, McEwen SC, Gee DG, et al. Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization. Nat Commun. 2018;9:3836.

  56. 56.

    Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2018;46(D1):D754–D61.

Download references


NGS library preparation, enrichment, sequencing and sequence analysis were performed by the Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. We sincerely thank FIMM’s sequencing and genotyping unit, especially Pekka Ellonen and Kati Donner for their efforts in producing the data. We also thank Sarang Talwelkar and Disha Malani for their input in improving the figures. This study has been funded by the Academy of Finland (128504, 259589 and 265097), MC-ITN EU-FP7 (607616) and Finnish Cultural Foundation (Ingrid, Toini and Olavi Martelius Grant 2018) for WH, Sigrid Juselius Foundation for JL and Jalmari and Rauha Ahokkas Foundation for VS. The funders had no further role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, nor in the decision to submit the paper for publication.

Author contributions

VS and WH wrote the paper and prepared the paper's tables and figures; WH designed the study; TP, JS, JL, IH, PJ, EI, ATH, ST, TDC and JK provided access to samples and data; VS, LUV, WH, MTH, ST and AOA performed the analysis. All authors have reviewed the paper and approved the final version to be published.

Author information

Correspondence to William Hennah.

Ethics declarations

Conflict of interest

WH has a co-appointment at Orion Pharma. The remaining authors declare no conflicts 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

Verify currency and authenticity via CrossMark