| 1. |
- Backlund, Lena, et al.
(författare)
-
Cognitive manic symptoms associated with the P2RX7 gene in bipolar disorder.
- 2011
-
Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 13:5-6, s. 500-8
-
Tidskriftsartikel (refereegranskat)abstract
- Several genetic loci have been suggested to be associated with bipolar disorder but results have been inconsistent. Studying associations between bipolar symptoms and candidate genes may better expose this relationship. Here we investigate the association between bipolar key symptoms and the P2RX7 gene.
|
|
| 2. |
- Backlund, L., et al.
(författare)
-
P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1
- 2012
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 27
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling. Objectives: To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients. Design: Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients. Participants: Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044). Results: P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912_A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls. Conclusions: Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.
|
|
| 3. |
- Brundin, L., et al.
(författare)
-
An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
- 2016
-
Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
|
|
| 4. |
- Ekman, Agneta, 1961, et al.
(författare)
-
Low density and high affinity of platelet [3H]paroxetine binding in women with bulimia nervosa.
- 2006
-
Ingår i: Psychiatry research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 142:2-3, s. 219-23
-
Tidskriftsartikel (refereegranskat)abstract
- Impaired serotonin transmission has been suggested to be implicated in the pathophysiology of bulimia nervosa. As an indirect measure of brain serotonergic activity, the binding of tritiated ligands to platelet serotonin transporters has been studied in bulimia nervosa as well as in other putatively serotonin-related psychiatric disorders. In this study, the density and affinity of platelet serotonin transporters were assessed in 20 women meeting the DSM-IV criteria for bulimia nervosa and in 14 controls without previous or ongoing eating disorder using [(3)H]paroxetine as a ligand. In comparison to controls, women with bulimia nervosa had a significantly reduced number of platelet binding sites (B(max) = 721 +/- 313 vs. 1145 +/- 293 fmol/mg protein) and an increase in the affinity for the ligand demonstrated by a lower dissociaton constant (K(d) = 33 +/- 10 vs. 44 +/- 10 pM). A significant correlation between B(max) and K(d) values was found in patients but not in controls. Our results support the notion that bulimia nervosa is associated with a reduction in platelet serotonin transporter density. In addition, our study is the first to report that this reduced transporter density in women with bulimia nervosa is accompanied by an increase in the affinity of the transporter for the ligand.
|
|
| 5. |
- Folkersen, Lasse, et al.
(författare)
-
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
-
Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
|
|
| 6. |
- Henningsson, Susanne, 1977, et al.
(författare)
-
Possible association between the androgen receptor gene and autism spectrum disorder.
- 2009
-
Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 34:5, s. 752-761
-
Tidskriftsartikel (refereegranskat)abstract
- Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.
|
|
| 7. |
- Hukic, Dzana Sudic, et al.
(författare)
-
Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes
- 2013
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction:Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function.Methodology:Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes. Results: The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model. Conclusion:Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population. © 2013 Hukic et al.
|
|
| 8. |
- Klaric, Lucija, et al.
(författare)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
|
|
| 9. |
- Lautner, Ronald, et al.
(författare)
-
Apolipoprotein e genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
- 2014
-
Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 71:10, s. 1183-91
-
Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown.
|
|
| 10. |
- Lautner, Ronald, et al.
(författare)
-
Preclinical effects of APOE ϵ4 on cerebrospinal fluid Aβ42 concentrations
- 2017
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: From earlier studies it is known that the APOE ϵ2/ϵ3/ϵ4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in APOE ϵ4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ϵ4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ϵ4-negative individuals and 43 years in heterozygous APOE ϵ4 carriers. Homozygous APOE ϵ4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE ϵ4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ϵ4 noncarriers already in early middle age. Homozygous APOE ϵ4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ϵ4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
|
|
