| 1. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 2. |
- Gracias, J., et al.
(författare)
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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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| 3. |
- Daníelsdóttir, Hilda Björk, et al.
(författare)
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Adverse Childhood Experiences and Adult Mental Health Outcomes
- 2024
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 81:6, s. 586-594
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders.OBJECTIVE: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding.DESIGN, SETTING, AND PARTICIPANTS: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023.EXPOSURES: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey.MAIN OUTCOMES AND MEASURES: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register.RESULTS: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11).CONCLUSIONS AND RELEVANCE: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.
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| 4. |
- Halvorsen, Peter, et al.
(författare)
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Health-related quality of life after surviving intensive care for COVID-19 : a prospective multicenter cohort study
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- In survivors of severe coronavirus disease 2019 (COVID-19) incomplete mental and physical recovery may considerably impact daily activities and health-related quality of life (HRQoL). HRQoL can be evaluated with the RAND-36 questionnaire, a multidimensional instrument that assesses physical and mental aspects of health in eight dimensions. The objective was to investigate HRQoL in intensive care patients previously treated for COVID-19 at three Nordic university hospitals, in a prospective multi-center cohort study. HRQoL was measured using RAND-36, 3-9 months after discharge from intensive care units (ICU). One hospital performed a second follow-up 12 months after discharge. A score under the lower limit of the 95% confidence interval in the reference cohorts was considered as significantly reduced HRQoL. We screened 542 and included 252 patients. There was more than twice as many male (174) as female (78) patients and the median age was 61 (interquartile range, IQR 52-69) years. Hypertension was the most common comorbidity observed in 132 (52%) patients and 121 (48%) patients were mechanically ventilated for a median of 8 (IQR 4-14) days. In RAND-36 physical functioning, physical role functioning, general health (p < 0.001 for all) and social functioning (p < 0.05) were below reference, whereas bodily pain, emotional role functioning and mental health were not. In a time-to-event analysis female sex was associated with a decreased chance of reaching the reference HRQoL in the physical function, bodily pain and mental health dimensions. Higher body mass index was found in the physical functioning dimension and hypertension in the physical functioning, vitality and social functioning dimensions. Similar results were seen for diabetes mellitus in general health, vitality and mental health dimensions, as well as pulmonary illness in the physical role functioning dimension and psychiatric diagnosis in the social functioning dimension. Mechanical ventilation was associated with a decreased likelihood of achieving reference HRQoL in the bodily pain and physical functioning dimensions. Patients treated in an ICU because of COVID-19 had lower HRQoL 3-9 months after ICU discharge than 95% of the general population. Physical dimensions were more severely affected than mental dimensions. Female sex and several comorbidities were associated with a slower rate of recovery.
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