| 1. |
- de Zwarte, Sonja M. C., et al.
(författare)
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Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 414-430
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Tidskriftsartikel (refereegranskat)abstract
- First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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| 2. |
- de Zwarte, Sonja M. C., et al.
(författare)
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The association between familial risk and brain abnormalities is disease specific : an ENIGMA-relatives study of schizophrenia and bipolar disorder
- 2019
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 86:7, s. 545-556
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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| 3. |
- Hou, Liping, et al.
(författare)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87 × 10(-9); odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53 × 10(-9); odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 4. |
- Purcell, Shaun M., et al.
(författare)
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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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| 5. |
- Schweinsberg, Martin, et al.
(författare)
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Same data, different conclusions : Radical dispersion in empirical results when independent analysts operationalize and test the same hypothesis
- 2021
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Ingår i: Organizational Behavior and Human Decision Processes. - : Elsevier BV. - 0749-5978 .- 1095-9920. ; 165, s. 228-249
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Tidskriftsartikel (refereegranskat)abstract
- In this crowdsourced initiative, independent analysts used the same dataset to test two hypotheses regarding the effects of scientists' gender and professional status on verbosity during group meetings. Not only the analytic approach but also the operationalizations of key variables were left unconstrained and up to individual analysts. For instance, analysts could choose to operationalize status as job title, institutional ranking, citation counts, or some combination. To maximize transparency regarding the process by which analytic choices are made, the analysts used a platform we developed called DataExplained to justify both preferred and rejected analytic paths in real time. Analyses lacking sufficient detail, reproducible code, or with statistical errors were excluded, resulting in 29 analyses in the final sample. Researchers reported radically different analyses and dispersed empirical outcomes, in a number of cases obtaining significant effects in opposite directions for the same research question. A Boba multiverse analysis demonstrates that decisions about how to operationalize variables explain variability in outcomes above and beyond statistical choices (e.g., covariates). Subjective researcher decisions play a critical role in driving the reported empirical results, underscoring the need for open data, systematic robustness checks, and transparency regarding both analytic paths taken and not taken. Implications for orga-nizations and leaders, whose decision making relies in part on scientific findings, consulting reports, and internal analyses by data scientists, are discussed.
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| 6. |
- Nehme, Ralda, et al.
(författare)
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The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia
- 2022
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
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| 7. |
- Ruderfer, Douglas M., et al.
(författare)
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Mosaic copy number variation in schizophrenia
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:9, s. 1007-1011
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n = 3518; control, n = 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
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| 8. |
- Charney, Alexander W, et al.
(författare)
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Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.
- 2019
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Ingår i: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 86:2, s. 110-119
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Tidskriftsartikel (refereegranskat)abstract
- Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
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| 9. |
- Dahlin, Anna M., 1979-, et al.
(författare)
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Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults : A Case-Control Study
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 28:7, s. 1252-1258
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA.Methods: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation.Results: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 (CDKN2B-AS1) locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratioG = 1.21; 95% confidence interval = 1.09–1.35; P = 5.8 × 10−4). In genome-wide analysis, an association with risk was suggested for 129 genetic variants (P <1 × 10−5).Conclusions: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts.Impact: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.
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| 10. |
- Genovese, Giulio, et al.
(författare)
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Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
- 2014
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Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 371:26, s. 2477-87
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
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