| 1. |
- Alnaes, Dag, et al.
(författare)
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Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk
- 2019
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Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748
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Tidskriftsartikel (refereegranskat)abstract
- ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and ParticipantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and MeasuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age,33.8[10.6] years; 68.6% male [n=790] and 31.4% female [n=361]) with 2010 healthy controls (mean [SD] age,32.6[10.4] years; 56.0% male [n=1126] and 44.0% female [n=884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t=3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age,55.9 [7.5] years; 48.2% male [n=6025] and 51.8% female [n=6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t=-3.00) but was not significantly associated with dispersion. Conclusions and RelevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
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| 2. |
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| 3. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 4. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 5. |
- Johansson, Martin M., et al.
(författare)
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Microarray Analysis of Copy Number Variants on the Human Y Chromosome Reveals Novel and Frequent Duplications Overrepresented in Specific Haplogroups
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The human Y chromosome is almost always excluded from genome-wide investigations of copy number variants (CNVs) due to its highly repetitive structure. This chromosome should not be forgotten, not only for its well-known relevance in male fertility, but also for its involvement in clinical phenotypes such as cancers, heart failure and sex specific effects on brain and behaviour.RESULTS:We analysed Y chromosome data from Affymetrix 6.0 SNP arrays and found that the signal intensities for most of 8179 SNP/CN probes in the male specific region (MSY) discriminated between a male, background signals in a female and an isodicentric male containing a large deletion of the q-arm and a duplication of the p-arm of the Y chromosome. Therefore, this SNP/CN platform is suitable for identification of gain and loss of Y chromosome sequences. In a set of 1718 males, we found 25 different CNV patterns, many of which are novel. We confirmed some of these variants by PCR or qPCR. The total frequency of individuals with CNVs was 14.7%, including 9.5% with duplications, 4.5% with deletions and 0.7% exhibiting both. Hence, a novel observation is that the frequency of duplications was more than twice the frequency of deletions. Another striking result was that 10 of the 25 detected variants were significantly overrepresented in one or more haplogroups, demonstrating the importance to control for haplogroups in genome-wide investigations to avoid stratification. NO-M214(xM175) individuals presented the highest percentage (95%) of CNVs. If they were not counted, 12.4% of the rest included CNVs, and the difference between duplications (8.9%) and deletions (2.8%) was even larger.CONCLUSIONS:Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome. Future association studies of the full spectrum of Y chromosome variants will demonstrate the potential involvement of gain or loss of Y chromosome sequence in different human phenotypes.
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| 6. |
- Jonsson, Erik G., et al.
(författare)
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DTNBP1, NRG1, DAOA, DAO and GRM3 Polymorphisms and Schizophrenia : An Association Study
- 2009
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Ingår i: Neuropsychobiology. - : S. Karger AG. - 0302-282X .- 1423-0224. ; 59:3, s. 142-150
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. Methods: In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. Results: One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. Conclusions: The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships. Copyright (C) 2009 S. Karger AG, Basel
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| 7. |
- Jönsson, Erik G., et al.
(författare)
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Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder : An association study
- 2008
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Ingår i: American journal of medical genetics. Part B, Neuropsychiatric genetics. - : Wiley. - 1552-4841. ; 147B:6, s. 976-982
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Tidskriftsartikel (refereegranskat)abstract
- Recent meta-analyses of the methylenetetrahydrofolate reductase gene (MTHFR) have suggested association between two of its functional single gene polymorphisms (SNPs, C677T and A1298C) and schizophrenia. Studies have also suggested association between MTHFR C677T and A1298C variation and bipolar disorder. In a replication attempt the MTHFR C677T and A1298C SNPs were analyzed in three Scandinavian schizophrenia case-control samples. In addition, Norwegian patients with bipolar disorder were investigated. There were no statistically significant allele or genotype case-control differences. The present Scandinavian results do not verify previous associations between the putative functional MTHFR gene polymorphisms and schizophrenia or bipolar disorder. However, when combined with previous studies in meta-analyses there is still evidence for association between the MTHFR C677T polymorphism. and schizophrenia. Additional studies are warranted to shed further light on these relationships. (c) 2007 Wiley-Liss, Inc.
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| 8. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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| 9. |
- Saetre, Peter, et al.
(författare)
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Association between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case-control sample
- 2008
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 106:2-3, s. 237-241
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Tidskriftsartikel (refereegranskat)abstract
- Disrupted-in-schizophrenia-1 (DISC1), located on chromosome 1q42.1, is linked to rare familial schizophrenia in a large Scottish family. The chromosomal translocation that segregates with the disease results in a truncated protein that impairs neurite outgrowth and proper development of the cerebral cortex, suggesting that lost DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia. DISC1 has been associated with schizophrenia in multiple populations, but there is little evidence of convergence across populations. In the present case-control study three Scandinavian samples of 837 individuals affected with schizophrenia and 1473 controls, were used in an attempt to replicate previously reported associations between single nucleotide polymorphisms (SNPs) in DISC1 and schizophrenia. No SNP with allele frequency above 10% was significantly associated with the disease after correction for multiple testing. However, the minor allele of rs3737597 (frequency 2%) in the 3'-untransiated region (UTR), previously identified as a risk allele in Finnish families, was significantly and consistently associated with the disorder across the three samples, (p-value corrected for multiple testing was 0.002). Our results suggest that a relatively uncommon DISC1 mutation, which increases the susceptibility for schizophrenia may be segregating in the Scandinavian population, and support the view that common DISC1 SNP alleles are unlikely to account for a substantial proportion of the genetic risk of the disease across populations of European descent.
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| 10. |
- Saetre, Peter, et al.
(författare)
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The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior : A Multi-Centre Case-Control Study and Meta-Analysis
- 2010
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Ingår i: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 153B:2, s. 387-396
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P=0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I-2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.
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