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Variants in regulatory elements of PDE4D associate with Major Mental Illness in the Finnish population

By Vishal Sinha, Liisa Ukkola-Vuoti, Alfredo Ortega-Alonso, Minna Torniainen-Holm, Sebastian Therman, Annamari Tuulio-Henriksson, Pekka Jylhä, Jaakko Kaprio, Iiris Hovatta, Erkki Isometsä, Tyrone D. Cannon, Jouko Lönnqvist, T. Paunio, J. Suvisaari, William Hennah

Posted 13 Aug 2018
bioRxiv DOI: 10.1101/390518 (published DOI: 10.1038/s41380-019-0429-x)

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 alluded to by these previous findings, we sequenced 945kb of the PDE4D genomic locus in 96 individuals, followed by two stages of genotyping across 6,668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4,570 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. Specifically, the cognitive domain was a factor score for quantitative neuropsychological endophenotypes related to verbal learning and memory (p=0.0078, β=-0.19). 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; post-prob=0.9; m-value=1.4), 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. Keywords: Schizophrenia; Psychotic disorders; Mood Disorders; PDE4D, Cognition

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