| 1. |
- Reinbold, C. S., et al.
(author)
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Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
- 2018
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In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 9
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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| 2. |
- Okada, S., et al.
(author)
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First application of superconducting transition-edge sensor microcalorimeters to hadronic atom X-ray spectroscopy
- 2016
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In: Progress of Theoretical and Experimental Physics. - : Oxford University Press (OUP). - 2050-3911. ; 2016:9
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Journal article (peer-reviewed)abstract
- High-resolution pionic atom X-ray spectroscopy was performed with an X-ray spectrometer based on a 240 pixel array of superconducting transition-edge sensor (TES) microcalorimeters at the φM1 beam line of the Paul Scherrer Institute. X-rays emitted by pionic carbon via the 4f → 3d transition and the parallel 4d → 3p transition were observed with a full width at half maximum energy resolution of 6.8 eV at 6.4 keV. The measured X-ray energies are consistent with calculated electromagnetic values which considered the strong interaction effect assessed via the Seki-Masutani potential for the 3p energy level, and favor the electronic population of two filled 1s electrons in the K-shell. Absolute energy calibration with an uncertainty of 0.1 eV was demonstrated under a high-rate hadron beam condition of 1.45 MHz. This is the first application of a TES spectrometer to hadronic atom X-ray spectroscopy and is an important milestone towards next-generation high-resolution kaonic atom X-ray spectroscopy.
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| 3. |
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| 4. |
- Zewinger, Stephen, et al.
(author)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Journal article (peer-reviewed)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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| 5. |
- Hou, Liping, et al.
(author)
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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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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Journal article (peer-reviewed)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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| 6. |
- Amare, Azmeraw T, et al.
(author)
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Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74
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Journal article (peer-reviewed)abstract
- Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
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| 7. |
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| 8. |
- Kalman, Janos L, et al.
(author)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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| 9. |
- Mattsson, M., et al.
(author)
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Personal factors in systemic sclerosis and their coverage by patient-reported outcome measures
- 2015
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In: European Journal of Physical and Rehabilitation Medicine. - 1827-1804. ; 51:4, s. 405-421
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Journal article (peer-reviewed)abstract
- Background. Systemic sclerosis (SSc) is an autoimmune disease where thickening of the skin can lead to reduced body function and limitations in activities. Severe forms can also affect and seriously damage inner organs. Patient-centred rehabilitation emphasises considerations of patients' background, experience and behavior which highlights the need to know if patient-reported outcome measures (PROMs) include such personal factors. Aim. To identify and describe personal factors in the experiences of functioning and health of persons with SSc and to examine if and to what extent PROMs in SSc research cover these factors. Design. Data from a qualitative study with focus group interviews were analysed. PROMs in SSc research were identified in a literature review between 2008-2013. Setting. Participants were recruited from outpatient clinics at rheumatology department. Population. Sixty-three patients with SSc from four European countries participated. Methods. Data from interviews were analysed using a structure of personal factors developed by Geyh et al. Identified PROMs were analysed and linked to main concepts, related to the personal factors, found in the interview data. Results. Nineteen main concepts were related to the area "patterns of experience and behaviour" in the personal factor structure, 16 to "thoughts and beliefs", nine to "feelings", one to "motives" and one to "personal history and biography", respectively. Among the 35 PROMs identified, 15 did not cover any of the identified concepts. Concepts within the area "feelings" were mostly covered by the PROMs. Five of the PROMs covered "patterns of experience and behaviour", while "motives" and "personal history and biography" were not covered at all. Four of the identified PROMs covered concepts within the areas "feelings", "thoughts and beliefs" and "patterns of experience and behaviour" in the same instrument. The Illness Cognition Questionnaire and Illness Behaviour Questionnaire were such PROMs. Conclusion. Patterns of experience and behaviour had the highest number of concepts related to personal factors, but few of the PROMs in SSc research covered these factors. Only a few PROMs covered several personal factors areas in the same instrument. Clinical Rehabilitation Impact. The results would be of value when developing core sets for outcome measurements in SSc.
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| 10. |
- Doriese, W B, et al.
(author)
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A practical superconducting-microcalorimeter X-ray spectrometer for beamline and laboratory science
- 2017
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In: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 88:5
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Journal article (peer-reviewed)abstract
- We describe a series of microcalorimeter X-ray spectrometers designed for a broad suite of measurement applications. The chief advantage of this type of spectrometer is that it can be orders of magnitude more efficient at collecting X-rays than more traditional high-resolution spectrometers that rely on wavelength-dispersive techniques. This advantage is most useful in applications that are traditionally photon-starved and/or involve radiation-sensitive samples. Each energy-dispersive spectrometer is built around an array of several hundred transition-edge sensors (TESs). TESs are superconducting thin films that are biased into their superconducting-to-normal-metal transitions. The spectrometers share a common readout architecture and many design elements, such as a compact, 65 mK detector package, 8-column time-division-multiplexed superconducting quantum-interference device readout, and a liquid-cryogen-free cryogenic system that is a two-stage adiabatic-demagnetization refrigerator backed by a pulse-tube cryocooler. We have adapted this flexible architecture to mate to a variety of sample chambers and measurement systems that encompass a range of observing geometries. There are two different types of TES pixels employed. The first, designed for X-ray energies below 10 keV, has a best demonstrated energy resolution of 2.1 eV (full-width-at-half-maximum or FWHM) at 5.9 keV. The second, designed for X-ray energies below 2 keV, has a best demonstrated resolution of 1.0 eV (FWHM) at 500 eV. Our team has now deployed seven of these X-ray spectrometers to a variety of light sources, accelerator facilities, and laboratory-scale experiments; these seven spectrometers have already performed measurements related to their applications. Another five of these spectrometers will come online in the near future. We have applied our TES spectrometers to the following measurement applications: synchrotron-based absorption and emission spectroscopy and energy-resolved scattering; accelerator-based spectroscopy of hadronic atoms and particle-induced-emission spectroscopy; laboratory-based time-resolved absorption and emission spectroscopy with a tabletop, broadband source; and laboratory-based metrology of X-ray-emission lines. Here, we discuss the design, construction, and operation of our TES spectrometers and show first-light measurements from the various systems. Finally, because X-ray-TES technology continues to mature, we discuss improvements to array size, energy resolution, and counting speed that we anticipate in our next generation of TES-X-ray spectrometers and beyond.
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| 11. |
- Krøll, L. S., et al.
(author)
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Has aerobic exercise effect on pain perception in persons with migraine and coexisting tension-type headache and neck pain? A randomized, controlled, clinical trial
- 2018
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In: European Journal of Pain. - : Wiley. - 1090-3801. ; 22:8, s. 1399-1408
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Journal article (peer-reviewed)abstract
- Background: A large subset of persons with migraine suffers from coexisting tension-type headache and neck pain which may adversely affect the prognosis of migraine. Aerobic exercise has been shown to decrease migraine burden in these persons. Therefore, the aim of this study was to investigate whether the effect of aerobic exercise in persons with migraine and coexisting tension-type headache and neck pain can be explained by changes in pain perception. Method: Seventy consecutively recruited persons with migraine and coexisting tension-type headache and neck pain were randomized into exercise group or control group. Aerobic exercise consisted of bike/cross-trainer/brisk walking for 45 min, three times/week for 3 months. Controls continued their usual daily activities. Pericranial tenderness, pain thresholds, supra-thresholds and temporal summation were assessed at baseline, after treatment and at follow-up (6 months from baseline). Results: Fifty-two persons with migraine and coexisting tension-type headache and neck pain completed the study. Aerobic exercise did not induce consistent changes in nociceptive pathways measured by pericranial tenderness, pressure pain thresholds and sensitivity to electrical stimulation. Conclusion: The effect of aerobic exercise cannot be explained by measurable effects on the pain modulation system. Thus, the positive effect on migraine burden may rather be explained by positive alteration of avoidance behaviour. Aerobic exercise can be recommended as a safe and inexpensive migraine treatment strategy. Significance: This study adds further knowledge about the positive effect of aerobic exercise for persons with migraine and coexisting tension-type headache and neck pain. This effect cannot be measured by changes in pain modulation, but may rather be explained by positive alteration of avoidance behaviour.
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| 12. |
- Mattsson, Malin, et al.
(author)
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Personal factors in systemic sclerosis and their coverage by patient-reported outcome measures : A multicentre European qualitative study and literature review
- 2015
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In: European Journal of Physical and Rehabilitation Medicine. - 1973-9087 .- 1973-9095. ; 51:4, s. 405-421
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease where thickening of the skin can lead to reduced body function and limitations in activities. Severe forms can also affect and seriously damage inner organs. Patient-centred rehabilitation emphasises considerations of patients’ background, experience and behavior which highlights the need to know if patient-reported outcome measures (PROMs) include such personal factors.AIM: To identify and describe personal factors in the experiences of functioning and health of persons with SSc and to examine if and to what extent PROMs in SSc research cover these factors.DESIGN: Data from a qualitative study with focus group interviews were analysed. PROMs in SSc research were identified in a literature review between 2008-2013.SETTING: Participants were recruited from outpatient clinics at rheumatology department.POPULATION: Sixty-three patients with SSc from four European countries participated.METHODS: Data from interviews were analysed using a structure of personal factors developed by Geyh et al. Identified PROMs were analysed and linked to main concepts, related to the personal factors, found in the interview data.RESULTS: Nineteen main concepts were related to the area “patterns of experience and behaviour” in the personal factor structure, 16 to “thoughts and beliefs”, nine to “feelings”, one to “motives” and one to “personal history and biography”, respectively. Among the 35 PROMs identified, 15 did not cover any of the identified concepts. Concepts within the area “feelings” were mostly covered by the PROMs. Five of the PROMs covered “patterns of experience and behaviour”, while “motives” and “personal history and biography” were not covered at all. Four of the identified PROMs covered concepts within the areas “feelings”, “thoughts and beliefs” and “patterns of experience and behaviour” in the same instrument. The Illness Cognition Questionnaire and Illness Behaviour Questionnaire were such PROMs.CONCLUSION: Patterns of experience and behaviour had the highest number of concepts related to personal factors, but few of the PROMs in SSc research covered these factors. Only a few PROMs covered several personal factors areas in the same instrument.CLINICAL REHABILITATION IMPACT: The results would be of value when developing core sets for outcome measurements in SSc.
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| 13. |
- Tibaek, S., et al.
(author)
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The effect of pelvic floor muscle training on sexual function in men with lower urinary tract symptoms after stroke
- 2015
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In: Topics in Stroke Rehabilitation. - 1074-9357. ; 22:3, s. 185-193
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Journal article (peer-reviewed)abstract
- Background: Erectile dysfunction and lower urinary tract symptoms (LUTS) are common sequelae in men after stroke. Objective: The objective of this study was to evaluate the effect of pelvic floor muscle training (PFMT) on measured erectile function as an indicator of sexuality in men with LUTS after stroke. Method: A sample of 516 men with stroke was invited to participate in this single-blinded, randomized controlled trial according to in- and exclusion criteria. This resulted in 31 participants who were randomized to either a Treatment Group (n=16) or a Control Group (n=15). The intervention included 12weeks of PFMT. The effect was measured on the International Index of Erectile Function (IIEF-5) questionnaire. Results: Thirty participants (median age: 68 years; interquartile range: 60-74 years) completed the study, 15 in each group. The results of the IIEF-5 sum score showed a significant improvement (P<0.04) from pre-test to post-test in the Treatment Group, but not in the Control Group. Within pre-test and 6-month follow-up, the median sum score decreased in both groups, worsened in the Control Group [ Treatment Group, 3 (17%) versus Control Group, 5 (31%)]. There were differences between the groups at post-test and at follow-up, but they were not statistically significant. Conclusion: The results showed that, as measured by erectile function in men with LUTS after stroke, PFMT may have short-term and long-term effect, although no statistically significant effect was demonstrated between the groups.
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| 14. |
- Törn, Carina, et al.
(author)
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Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65-0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01-1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05-2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43-0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75-5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes.
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