Biology subjects

Hamalainen, E.

Publications and source records attributed to Hamalainen, E..

4 recordsLinked to original sources

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗

bioRxiv2021

Automatic segmentation of the rat brain hippocampus in MRI after traumatic brain injury

AO_SCPLOWBSTRACTC_SCPLOWRegistration-based methods are commonly used in the anatomical segmentation of magnetic resonance (MR) brain images. However, they are sensitive to the presence of deforming brain pathologies that may interfere with the alignment of the atlas image with the target image. Our goal was to develop an algorithm for automated segmentation of the normal and injured rat hippocampus. We implemented automated segmentation using a U-Net-like Convolutional Neural Network (CNN). of sham-operated experimental controls and rats with lateral-fluid-percussion induced traumatic brain injury (TBI) on MR images and trained ensembles of CNNs. Their performance was compared to three registration-based methods: single-atlas, multi-atlas based on majority voting and Similarity and Truth Estimation for Propagated Segmentations (STEPS). Then, the automatic segmentations were quantitatively evaluated using six metrics: Dice score, Hausdorff distance, precision, recall, volume similarity and compactness using cross-validation. Our CNN and multi-atlas -based segmentations provided excellent results (Dice scores > 0.90) despite the presence of brain lesions, atrophy and ventricular enlargement. In contrast, the performance of singe-atlas registration was poor (Dice scores < 0.85). Unlike registration-based methods, which performed better in segmenting the contralateral than the ipsilateral hippocampus, our CNN-based method performed equally well bilaterally. Finally, we assessed the progression of hippocampal damage after TBI by applying our automated segmentation tool. Our data show that the presence of TBI, time after TBI, and whether the location of the hippocampus was ipsilateral or contralateral to the injury explained hippocampal volume (p = 0.029, p < 0.001, and p < 0.001 respectively).

bioinformatics↗

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↗

bioRxiv2017

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.\n\nMain abbreviations

genetics↗