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- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 3. |
- Ising, Erik, et al.
(author)
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Impaired vibrotactile sense in children and adolescents with type 1 diabetes – Signs of peripheral neuropathy
- 2018
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Journal article (peer-reviewed)abstract
- Objective To investigate whether multi-frequency vibrometry can identify individuals with elevated vibration perception thresholds (VPTs), reflecting impaired vibrotactile sense, among children and adolescents with type 1 diabetes. Methods In 72 pediatric patients with type 1 diabetes, VPTs were evaluated for seven frequencies on two sites of the hand, and five frequencies on two sites of the foot. Z-scores, based on previously collected reference data, were calculated. Perception to light touch was investigated using monofilaments. Subjects’ characteristics were analyzed in comparison to normal and impaired vibrotactile sense. Results Subjects’ median age, disease duration and age at disease onset were 12.8, 5.3 and 6.9 years, respectively. A total of 13 out of 72 (18%) subjects had impaired vibrotactile sense on at least one foot site. Impaired vibrotactile sense was more common among subjects treated with multiple daily insulin injections (MDI) compared to subjects treated with continuous subcutaneous insulin infusion (CSII) (p = 0.013). Age at disease onset was higher among subjects with impaired vibrotactile sense (p = 0.046). No significant correlations were found with gender, HbA1c or duration of diabetes. Conclusions Impaired vibrotactile sense, mirroring diabetic peripheral neuropathy, was found in 1/5 of the children and adolescents in the study, and was more common in patients treated with MDI than in subjects treated with CSII.
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| 6. |
- Ising, Erik, et al.
(author)
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Quantification of heat shock proteins in the posterior interosseous nerve among subjects with type 1 and type 2 diabetes compared to healthy controls
- 2023
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In: Frontiers in Neuroscience. - : FRONTIERS MEDIA SA. - 1662-4548 .- 1662-453X. ; 17
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Journal article (peer-reviewed)abstract
- Introduction: Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 (T1D) and type 2 diabetes (T2D). No cure for DPN is available, but several potential targets have been proposed for treatment. Heat shock proteins (HSPs) are known to respond to both hyper- and hypoglycemia. DPN can be diagnosed using electrophysiology and studied using peripheral nerve biopsies.Aim: This study aimed to analyze the presence and patterns of HSPs in peripheral nerve biopsies from subjects with T1D, T2D, and healthy controls.Methods: Posterior interosseous nerves (PIN) from a total of 56 subjects with T1D (n = 9), with T2D (n = 24), and without diabetes (i.e., healthy controls, n = 23) were harvested under local anesthesia and prepared for quantitative mass spectrometry analysis. Protein intensities were associated with electrophysiology data of the ulnar nerve and morphometry of the same PIN, and differences in protein intensities between groups were analyzed.Results: In total, 32 different HSPs were identified and quantified in the nerve specimens. No statistically significant differences were observed regarding protein intensities between groups. Furthermore, protein intensities did not correlate with amplitude or conduction velocity in the ulnar nerve or with the myelinated nerve fiber density of PIN.Conclusion: Quantitative proteomics can be used to study HSPs in nerve biopsies, but no clear differences in protein quantities were observed between groups in this cohort.
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| 7. |
- Ising, Erik, et al.
(author)
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Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes
- 2021
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In: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 38:11
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Journal article (peer-reviewed)abstract
- AIMS: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes (T2D). The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN.METHODS: A quantitative mass spectrometry-based proteomics analysis was made of peripheral nerves from age- and gender-matched living human male tissue donors; nine T2D subjects, with decreased sural nerve action potentials indicating DPN, and six controls without T2D, with normal electrophysiology results.RESULTS: A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between T2D and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins were made in order to find clusters of similar proteins in T2D subjects and healthy controls.CONCLUSIONS: This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without T2D, which may aid in finding biomarkers of importance to DPN development.
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| 8. |
- Ising, Erik, et al.
(author)
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Vibrotactile sense in children with type 1 diabetes
- 2017
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:Suppl 1, s. 153-153
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Conference paper (peer-reviewed)abstract
- Introduction: Diabetic peripheral neuropathy (DPN) is a devastating complication to DM, potentially leading to diabetic foot ulcers. Studies using electrophysiology shows high occurrence of subclinical DPN among children, but it is unclear when and how to start screen children with T1D for DPN. Aim: To investigate whether evaluation of the vibrotactile sense, using a multi-frequency method, in the right hand and foot can detect underlying sensory neuropathy in children with T1D, and whether the DPN has any correlation to, for example, gender, age, duration of disease and metabolic control measured as HbA1c values. Methods: Vibration perception thresholds (VPTs), resulting in curves and numeric values, were evaluated using a VibroSense Meter. VPTs were related to normative data obtained from healthy children, and evaluated in relation to different characteristics. Subjects were 8-18 years old T1D patients. Subjects that failed to produce at least one visibly evaluable curve were excluded. Z-values of >2.0 were considered pathological. Subjects needed at least 3 pathological frequencies at the same site in order to claim the examined site as pathological. Results: 73 children (boys = 39) with mean age 13.2 [8.39-17.96] years and duration of T1D of 5.9 [0.54-14.58] years met the inclusion and exclusion criteria. On index and little fingers, 5/73 (6.8%) and 4/73 (5.5%) children respectively had pathological values. On metatarsal heads one and five, 9/73 (12.3%) children had pathological values on each site. In total 15/73 (21.0%) children had at least one pathological site and 3 (4.1%) had pathological values on all sites examined. Presence of pathological values on all sites correlated to the height of the subject (p = 0.011) but not to gender, duration of disease or HbA1c. Conclusion: Our findings suggests that DPN, reflected by impaired vibrotactile sense, is present among children with T1D. Since up to 21% of the children showed signs of impaired vibrotactile sense, it may be important to screen children with T1D for early detection of DPN.
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| 9. |
- Ising, Erik, et al.
(author)
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Vibrotactile sense might improve over time in paediatric subjects with type 1 diabetes - a mid-term follow-up using multifrequency vibrometry
- 2022
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In: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 111:2, s. 411-417
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Journal article (peer-reviewed)abstract
- AimImpaired vibrotactile sense, mirroring diabetic peripheral neuropathy, is present among children and adolescents with type 1 diabetes. This study aims to re-examine the vibrotactile sense of paediatric type 1 diabetes subjects in order to evaluate any alterations in the vibrotactile sense over time.MethodsA VibroSense Meter I device was used to determine the vibrotactile perception thresholds (VPTs) for seven frequencies from the pulp of index and little fingers and for five frequencies from metatarsal heads one and five on the sole of the foot, of 37 children and adolescents with type 1 diabetes, previously examined in a larger cohort. Subjects were followed up after a median time of 30 months. Z-scores of VPTs were calculated using previously collected normative data.ResultsVPTs improved over time at low frequencies (especially 16 Hz) on the foot, while not being statistically significant different on the rest of the frequencies, either on hand or foot. VPTs were not correlated to HbA1c.ConclusionA mid-term follow-up of vibrotactile sense in paediatric subjects with type 1 diabetes shows a conceivable normalization of previously impaired vibrotactile sense on some frequencies on the foot, indicating that vibrotactile sense might fluctuate over time.
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| 10. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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