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