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Sökning: WFRF:(Koller A) > Umeå universitet

  • Resultat 1-9 av 9
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1.
  • Blokland, G. A. M., et al. (författare)
  • Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
  • 2022
  • Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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2.
  • de Jong, S, et al. (författare)
  • Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
  • 2018
  • Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
  • Tidskriftsartikel (refereegranskat)abstract
    • Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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5.
  • Estrada, Karol, et al. (författare)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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6.
  • Mullins, Niamh, et al. (författare)
  • GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
  • 2019
  • Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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7.
  • Niggemann, B., et al. (författare)
  • Five-year follow-up on the PAT study : specific immunotherapy and long-term prevention of asthma in children
  • 2006
  • Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 61:7, s. 855-859
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:  A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up – 2 years after termination of immunotherapy.Methods:  A total of 183 children, aged 6–14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation.Results:  The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3–5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01).Conclusion:  Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.
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8.
  • Koller-Smith, Louise I. M., et al. (författare)
  • Comparing very low birth weight versus very low gestation cohort methods for outcome analysis of high risk preterm infants
  • 2017
  • Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431 .- 1471-2431. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Compared to very low gestational age (<32 weeks, VLGA) cohorts, very low birth weight (<1500 g; VLBW) cohorts are more prone to selection bias toward small-for-gestational age (SGA) infants, which may impact upon the validity of data for benchmarking purposes. Method: Data from all VLGA or VLBW infants admitted in the 3 Networks between 2008 and 2011 were used. Two-thirds of each network cohort was randomly selected to develop prediction models for mortality and composite adverse outcome (CAO: mortality or cerebral injuries, chronic lung disease, severe retinopathy or necrotizing enterocolitis) and the remaining for internal validation. Areas under the ROC curves (AUC) of themodels were compared. Results: VLBW cohort (24,335 infants) had twice more SGA infants (20.4% vs. 9.3%) than the VLGA cohort (29,180 infants) and had a higher rate of CAO (36.5% vs. 32.6%). The two models had equal prediction power for mortality and CAO (AUC 0.83), and similarly for all other cross-cohort validations (AUC 0.81-0.85). Neither model performed well for the extremes of birth weight for gestation (<1500 g and >= 32 weeks, AUC 0.50-0.65; >= 1500 g and >= 32 weeks, AUC 0.60-0.62). Conclusion: There was no difference in prediction power for adverse outcome between cohorting VLGA or VLBW despite substantial bias in SGA population. Either cohorting practises are suitable for international benchmarking.
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9.
  • Koller, Timm O, et al. (författare)
  • Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes
  • 2022
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 50:19, s. 11285-11300
  • Tidskriftsartikel (refereegranskat)abstract
    • HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.
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