Biology subjects

Torniainen-Holm, M.

Publications and source records attributed to Torniainen-Holm, M..

3 recordsLinked to original sources

bioRxiv2018

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

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 the 1.5Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals, and 79 independent chromosomes), 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 (g-score p=0.044, beta=-0.033). Specifically, the cognitive domains represented verbal learning and memory (p=0.0091, beta=-0.044) and verbal working memory (p=0.0062, beta=-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.

genetics↗

bioRxiv2018

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

The contribution of de novo and ultra-rare genetic variants in severe and moderate intellectual disability (ID) has been extensively studied whereas the genetic architecture of mild ID has been less well characterized. To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals.\n\nWe show that rare damaging variants in genes known to be associated with cognitive defects are observed more often in severe (27%) than in mild ID (13%) patients (p-value: 7.0e-4). We further observed a significant enrichment of protein truncating variants in loss-of-function intolerant genes, as well as damaging missense variants in genes not yet associated with cognitive defects (OR: 2.1, p-value: 3e-8). For the first time to our knowledge, we show that a common variant polygenic load significantly contributes to all severity forms of ID. The heritability explained was the highest for educational attainment (EDU) in mild ID explaining 2.2% of the heritability on liability scale. For more severe ID it was lower at 0.6%. Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria. The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection.

genetics↗

bioRxiv2016

The NDE1 Genomic Locus Affects Treatment of Psychiatric Illness through Gene Expression Changes Related to MicroRNA-484

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the \"DISC1 network\". Here, we utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, whilst prescription medication information has been collected over a ten-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2,908 probes (2,542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p=3.0x10-8), located on a non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

genetics↗