2019
DOI: 10.1038/s41380-019-0429-x
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Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population

Abstract: doi: bioRxiv preprint (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; nor in the collection, analysis, and interpretation of data, in the writing of the report, nor in the decision to submit the paper for publication.

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Cited by 9 publications
(10 citation statements)
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References 55 publications
(67 reference statements)
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“…Postmortem studies of the dlPFC from subjects with schizophrenia have corroborated these findings revealing a decrement in the density of dendritic spines and dendritic arbors in dlPFC deep layer III (Garey et al, 1998;Glantz and Lewis, 2000), and associated with mitochondrial dysfunction and a hypometabolic phenotype (Arion et al, 2015;Hoftman et al, 2017). Directly relevant to the current study, single-nucleotide polymorphisms (SNPs) in PDE4D that decrease mRNA expression are associated with increased risk of schizophrenia and cognitive impairment in mental illness (Tomppo et al, 2009;Sinha et al, 2019). PDE4D has been etiologically implicated in the pathogenesis of other neuropsychiatric diseases associated with PFC dysfunction, with genome-wide association studies identifying point mutations in PDE4D with intellectual disability, major depression and anxiety disorders (Shifman et al, 2008;Lee et al, 2012b;Lindstrand et al, 2014).…”
Section: Clinical Relevance To the Neuropathology Of Schizophrenia Ansupporting
confidence: 58%
“…Postmortem studies of the dlPFC from subjects with schizophrenia have corroborated these findings revealing a decrement in the density of dendritic spines and dendritic arbors in dlPFC deep layer III (Garey et al, 1998;Glantz and Lewis, 2000), and associated with mitochondrial dysfunction and a hypometabolic phenotype (Arion et al, 2015;Hoftman et al, 2017). Directly relevant to the current study, single-nucleotide polymorphisms (SNPs) in PDE4D that decrease mRNA expression are associated with increased risk of schizophrenia and cognitive impairment in mental illness (Tomppo et al, 2009;Sinha et al, 2019). PDE4D has been etiologically implicated in the pathogenesis of other neuropsychiatric diseases associated with PFC dysfunction, with genome-wide association studies identifying point mutations in PDE4D with intellectual disability, major depression and anxiety disorders (Shifman et al, 2008;Lee et al, 2012b;Lindstrand et al, 2014).…”
Section: Clinical Relevance To the Neuropathology Of Schizophrenia Ansupporting
confidence: 58%
“…Studies in mice have placed PDE4D downstream from the calcium influx through the N -methyl-D-aspartate receptor in a pathway that leads to activation of calcium/calmodulin adenylate cyclase and phosphorylation of the cAMP-response element binding protein (CREB) transcription factor (Bailey et al, 1996; Kandel, 2009; Zhang et al, 2018). PDE4D is expressed in layer II/III cortical pyramidal neurons (Cherry and Davis, 1999), which play an important role in major mental disorders including fragile X syndrome, autism, and depression (Sinha et al, 2019; Zamarbide et al, 2019; Zhu et al, 2019). Furthermore, pharmacological inhibition or genetic knockdown of PDE4D activity promotes spine maturation in healthy adult mice and in a genetic model of fragile X syndrome (Gurney et al, 2017; Baumgärtel et al, 2018).…”
Section: Introductionmentioning
confidence: 99%
“…Also, NTM encodes neurotrimin and is linked to autism spectrum disorders and attention deficit hyperactivity disorders [25,26]. The PDE4D encodes phosphodiesterase 4D and is linked to schizophrenia, psychosis, acrodysostosis, and neuroticism [27][28][29]. Notably, PDE4D Inhibitors are in clinical trials for the treatment of Alzheimer's disease and Fragile X syndrome [30,31].…”
Section: Discussionmentioning
confidence: 99%