Variants in regulatory elements of PDE4D associate with Major Mental Illness in the Finnish population
Tyrone D. Cannon,
Posted 13 Aug 2018
bioRxiv DOI: 10.1101/390518 (published DOI: 10.1038/s41380-019-0429-x)
Posted 13 Aug 2018
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
- Downloaded 472 times
- Download rankings, all-time:
- Site-wide: 63,780
- In genetics: 2,830
- Year to date:
- Site-wide: 75,970
- Since beginning of last month:
- Site-wide: 44,268
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!