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  • Resultat 1-10 av 14
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1.
  • Grasby, KL, et al. (författare)
  • The genetic architecture of the human cerebral cortex
  • 2020
  • Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 367:6484, s. 1340-
  • Tidskriftsartikel (refereegranskat)
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2.
  • Hughes, T., et al. (författare)
  • Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder
  • 2018
  • Ingår i: Translational Psychiatry. - 2158-3188. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis pvalues: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3's association with bipolar disorder.
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3.
  • Schwarz, Emanuel, et al. (författare)
  • Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder
  • 2019
  • Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188 .- 2158-3188. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.
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4.
  • Sonderby, Ida E., et al. (författare)
  • Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
  • Tidskriftsartikel (refereegranskat)abstract
    • Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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5.
  • Córdova-Palomera, Aldo, et al. (författare)
  • Genetic control of variability in subcortical and intracranial volumes
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578.
  • Tidskriftsartikel (refereegranskat)abstract
    • Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.
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6.
  • Hughes, Timothy, et al. (författare)
  • A Loss-of-Function Variant in a Minor Isoform of ANK3 Protects Against Bipolar Disorder and Schizophrenia.
  • 2016
  • Ingår i: Biological psychiatry. - 1873-2402. ; 80:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Ankyrin-3 (ANK3) was one of the first genes to reach significance in a bipolar disorder genome-wide association study. Many subsequent association studies confirmed this finding and implicated this gene in schizophrenia. However, the exact nature of the role of ANK3 in the pathophysiology remains elusive. In particular, the specific isoforms involved and the nature of the imbalance are unknown.
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  • Resultat 1-10 av 14
  • [1]2Nästa

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