| 1. |
- Bryois, J., et al.
(författare)
-
Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Elvsashagen, T, et al.
(författare)
-
The genetic architecture of human brainstem structures and their involvement in common brain disorders
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4016-
-
Tidskriftsartikel (refereegranskat)abstract
- Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- van der Meer, D, et al.
(författare)
-
Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes
- 2020
-
Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 25:11, s. 3053-3065
-
Tidskriftsartikel (refereegranskat)abstract
- The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.
|
|
| 9. |
- 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.
|
|
| 10. |
- Delfin, Carl, 1986, et al.
(författare)
-
Exploring the Effects of an Acute Dose of Antipsychotic Medication on Motivation-mediated BOLD Activity Using fMRI and a Perceptual Decision-making Task
- 2020
-
Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 440, s. 146-159
-
Tidskriftsartikel (refereegranskat)abstract
- The left inferior frontal gyrus and the bilateral ventral striatum are thought to be involved in motivation-mediated decision-making. Antipsychotics may influence this relationship, and atypical antipsychotics improve secondary negative symptoms in schizophrenia, such as loss of motivation, although the acute effects of pharmacological medication on motivation are not fully understood. In this single-blinded, randomized controlled trial, 49 healthy volunteers were randomized into three groups to receive a single dose of haloperidol, aripiprazole or placebo. Between 4.0 and 5.6 h later, participant's brain blood-oxygen-level dependent (BOLD) activity was recorded using functional magnetic resonance imaging (fMRI) while completing a perceptual decision-making fMRI task consisting of one neutral and one motivated condition. Response bias, reflecting the participant's willingness to say that the target stimulus is present, was calculated using signal detection theory. Concurrent with widespread changes in BOLD signal in the motivated vs. neutral condition, a less conservative, mathematically optimal response bias was observed in the motivated condition across the whole sample. Within-group differences in BOLD signal in the left inferior frontal gyrus and bilateral ventral striatum were observed between conditions in the aripiprazole and haloperidol groups, but not in the placebo group. No robust between-group differences in brain activity in the left inferior frontal gyrus or the bilateral ventral striatum were found. Overall, we found no robust evidence for an effect of either aripiprazole or haloperidol on motivationally mediated behavior. An interesting pattern of correlations possibly related to pharmacologically induced alterations in the dopamine system was observed, although findings remain inconclusive and must be replicated in larger samples. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
|
|
