RT Journal Article SR Electronic T1 Variants in regulatory elements of PDE4D associate with Major Mental Illness in the Finnish population JF bioRxiv FD Cold Spring Harbor Laboratory SP 390518 DO 10.1101/390518 A1 Vishal Sinha A1 Liisa-Ukkola Vuoti A1 Alfredo Ortega-Alonso A1 Minna Torniainen-Holm A1 Sebastian Therman A1 Annamari Tuulio-Henriksson A1 Pekka Jylhä A1 Jaakko Kaprio A1 Iiris Hovatta A1 Erkki Isometsä A1 Tyrone D. Cannon A1 Jouko Lönnqvist A1 Tiina Paunio A1 Jaana Suvisaari A1 William Hennah YR 2018 UL http://biorxiv.org/content/early/2018/08/13/390518.abstract AB 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.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. This study has been funded by the Academy of Finland (128504, 259589 and 265097), and MC-ITN EU-FP7 (607616) 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.