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- Momozawa, Y, et al.
(författare)
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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
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Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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| 2. |
- Manyukhina, V. O., et al.
(författare)
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Globally elevated excitation-inhibition ratio in children with autism spectrum disorder and below-average intelligence
- 2022
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Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Altered neuronal excitation-inhibition (E-I) balance is strongly implicated in ASD. However, it is not known whether the direction and degree of changes in the E-I ratio in individuals with ASD correlates with intellectual disability often associated with this developmental disorder. The spectral slope of the aperiodic 1/f activity reflects the E-I balance at the scale of large neuronal populations and may uncover its putative alternations in individuals with ASD with and without intellectual disability. Methods Herein, we used magnetoencephalography (MEG) to test whether the 1/f slope would differentiate ASD children with average and below-average (< 85) IQ. MEG was recorded at rest with eyes open/closed in 49 boys with ASD aged 6-15 years with IQ ranging from 54 to 128, and in 49 age-matched typically developing (TD) boys. The cortical source activity was estimated using the beamformer approach and individual brain models. We then extracted the 1/f slope by fitting a linear function to the log-log-scale power spectra in the high-frequency range. Results The global 1/f slope averaged over all cortical sources demonstrated high rank-order stability between the two conditions. Consistent with previous research, it was steeper in the eyes-closed than in the eyes-open condition and flattened with age. Regardless of condition, children with ASD and below-average IQ had flatter slopes than either TD or ASD children with average or above-average IQ. These group differences could not be explained by differences in signal-to-noise ratio or periodic (alpha and beta) activity. Limitations Further research is needed to find out whether the observed changes in E-I ratios are characteristic of children with below-average IQ of other diagnostic groups. Conclusions The atypically flattened spectral slope of aperiodic activity in children with ASD and below-average IQ suggests a shift of the global E-I balance toward hyper-excitation. The spectral slope can provide an accessible noninvasive biomarker of the E-I ratio for making objective judgments about treatment effectiveness in people with ASD and comorbid intellectual disability.
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