| 1. |
- Blokland, G. A. M., et al.
(author)
-
Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
-
In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
-
Journal article (peer-reviewed)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
|
|
| 2. |
- Virtanen, Marianna, et al.
(author)
-
Long working hours and change in body weight : analysis of individual-participant data from 19 cohort studies
- 2020
-
In: International Journal of Obesity. - : Nature Publishing Group. - 0307-0565 .- 1476-5497. ; 44:6, s. 1368-1375
-
Journal article (peer-reviewed)abstract
- Objective: To examine the relation between long working hours and change in body mass index (BMI). Methods: We performed random effects meta-analyses using individual-participant data from 19 cohort studies from Europe, US and Australia (n = 122,078), with a mean of 4.4-year follow-up. Working hours were measured at baseline and categorised as part time (<35 h/week), standard weekly hours (35–40 h, reference), 41–48 h, 49–54 h and ≥55 h/week (long working hours). There were four outcomes at follow-up: (1) overweight/obesity (BMI ≥ 25 kg/m2) or (2) overweight (BMI 25–29.9 kg/m2) among participants without overweight/obesity at baseline; (3) obesity (BMI ≥ 30 kg/m2) among participants with overweight at baseline, and (4) weight loss among participants with obesity at baseline. Results: Of the 61,143 participants without overweight/obesity at baseline, 20.2% had overweight/obesity at follow-up. Compared with standard weekly working hours, the age-, sex- and socioeconomic status-adjusted relative risk (RR) of overweight/obesity was 0.95 (95% CI 0.90–1.00) for part-time work, 1.07 (1.02–1.12) for 41–48 weekly working hours, 1.09 (1.03–1.16) for 49–54 h and 1.17 (1.08–1.27) for long working hours (P for trend <0.0001). The findings were similar after multivariable adjustment and in subgroup analyses. Long working hours were associated with an excess risk of shift from normal weight to overweight rather than from overweight to obesity. Long working hours were not associated with weight loss among participants with obesity. Conclusions: This analysis of large individual-participant data suggests a small excess risk of overweight among the healthy-weight people who work long hours.
|
|
| 3. |
|
|
| 4. |
- Aoki, Y, et al.
(author)
-
Fine Tuning of Phosphorothioate Inclusion in 2'-O-Methyl Oligonucleotides Contributes to Specific Cell Targeting for Splice-Switching Modulation
- 2021
-
In: Frontiers in physiology. - : Frontiers Media SA. - 1664-042X. ; 12, s. 689179-
-
Journal article (peer-reviewed)abstract
- Splice-switching antisense oligonucleotide- (SSO-) mediated correction of framedisrupting mutation-containing premessenger RNA (mRNA) transcripts using exon skipping is a highly promising treatment method for muscular diseases such as Duchenne muscular dystrophy (DMD). Phosphorothioate (PS) chemistry, a commonly used oligonucleotide modification, has been shown to increase the stability of and improve the pharmacokinetics of SSOs. However, the effect of PS inclusion in 2′-O-methyl SSOs (2OMe) on cellular uptake and splice switching is less well-understood. At present, we demonstrate that the modification of PS facilitates the uptake of 2OMe in H2k-mdx myoblasts. Furthermore, we found a dependency of SSO nuclear accumulation and high splice-switching activity on PS inclusion in 2OMe (2OMePS), as tested in various reporter cell lines carrying pLuc/705. Increased exon-inclusion activity was observed in muscle, neuronal, liver, and bone cell lineages via both the gymnotic uptake and lipofection of 2OMePS. Using the photoactivatable ribonucleoside-enhanced crosslinking and a subsequent proteomic approach, we identified several 2OMePS-binding proteins, which are likely to play a role in the trafficking of 2OMePS to the nucleus. Ablation of one of them, Ncl by small-interfering RNA (siRNA) enhanced 2OMePS uptake in C2C12 myoblasts and upregulated luciferase RNA splicing in the HeLa Luc/705 reporter cell line. Overall, we demonstrate that PS inclusion increases nuclear delivery and splice switching in muscle, neuronal, liver, and bone cell lineages and that the modulation of 2OMePS-binding partners may improve SSO delivery.
|
|
| 5. |
- Asuman, Derek, et al.
(author)
-
Labour market consequences of an early-onset disability : the case of cerebral palsy
- 2024
-
In: Applied Economics. - : Informa UK Limited. - 0003-6846 .- 1466-4283.
-
Journal article (peer-reviewed)abstract
- The labour market consequences of early-onset or congenital disabilities have received little attention in the literature. In this paper, we study the consequences of cerebral palsy (CP), a lifelong early onset disability, and pathways through which it affects labour outcomes. We use data from multiple linked Swedish National Population Registers between 1990 and 2015 and apply both regression and mediation analysis. Our results show, as expected, strong negative consequences of CP on labour outcomes, and that the consequences have increased over time. The social insurance system, we find, compensates for some of the losses through non-work-related benefits. The results also suggest that the direct effects of CP per se have prominent impact on labour market outcomes. Thus, given the same level of mediators, persons with CP will have lower labour outcomes compared to persons without CP. Our results draw attention to the widening labour market consequences of CP in Sweden.
|
|
| 6. |
- Ax, AK, et al.
(author)
-
Cost effectiveness of high versus low-to-moderate intensity exercise during oncological treatment : The Phys-Can RCT
- 2022
-
In: Annals of Oncology. - : Elsevier BV. - 0923-7534.
-
Conference paper (peer-reviewed)abstract
- Background A cost-effectiveness analysis, considering both costs and health outcomes of interventions, are important for decision-making and implementation in the health care. Exercise during oncological treatment is beneficial for health and have been found to counteract side effects of treatment. The Swedish Phys-Can RCT compared a six-month exercise program combining supervised resistance training and homebased endurance training of high-intensity (HI) versus low-to-moderate intensity (LMI), with or without additional behaviour change support. At post intervention, HI yielded small improvements of fitness and physical fatigue compared with LMI. At 18 months, no differences were found in total costs between the intensities. However, knowledge of the cost effectiveness in exercise interventions with regard to intensity is limited. In this study, we aimed to evaluate the long-term cost-effectiveness of an exercise program at HI versus LMI during oncological treatment. Methods A cost-effectiveness analysis was undertaken from a societal perspective for 18 months. 189 (n=99 HI and n=90 LMI) participants with breast, colorectal, or prostate cancer were included from the Phys-Can RCT. Health outcomes were measured as quality-adjusted life years (QALYs), using EQ-5D-5L at baseline, six months and 18 months. Costs included the exercise intervention, health care utilisation and productivity loss. Results At 18 months, the total cost per participant did not differ significantly between HI (€27,314) and LMI exercise (€29,788). There was no significant difference in health outcome between the intensities. On average HI generated 1.190 (SD = 0.223) QALYs and LMI 1.185 (SD = 0.211) QALYs for 18 months, meaning HI led to an additional 0.005 QALYs. The incremental cost-effectiveness ratio (ICER) indicates that HI was more effective and saved costs compared with LMI. Conclusions The uncertainty around the ICER was large, however our results indicates that HI exercise was cost-effective compared to LMI exercise at longer term since there was lower total costs per QALY gained. Thus, we suggest that exercise with its health benefits may be implemented regardless of intensity.
|
|
| 7. |
- Borneskog, Catrin, et al.
(author)
-
Changes in sexual behavior among high-school students over a 40-year period
- 2021
-
In: Scientific Reports. - : Nature Research. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- The aim of this study was to investigate sexual behavior, contraceptive use, risk factors as well as sources of sex information among first-year high-school students in Sweden. Secondly, to assess differences between genders and study programs as well as changes over a 40-year period. A repeated cross-sectional survey was conducted in two cities. A questionnaire comprising 77 items was used. The study population consisted of 415 students (63.4% females). The median age of sexual intercourse was 15 years. In total, 37% had had sexual intercourse, compared to 56.3% in 2009 and 45% in 1999 (p < 0.001), and the proportion of students who had their first sexual intercourse was not influenced by gender. More students in vocational programs (46.3%), compared to theoretical (33.3%), had experience of at least one sexual intercourse (p = 0.019). The same extend of contraception use at first and latest intercourse was reported, compared to previous studies. Forty-nine percent were mostly informed about sex from the internet, while in previous years, magazines, family and youth clinics were the main information sources. Comparing over time, students were in general less sexually experienced and less engaged in non-penetrative sex and physical intimacy. These findings call for a new approach, when designing sex and relationship education and health-care counseling in adolescents.
|
|
| 8. |
|
|
| 9. |
- Dahlqvist, Johanna, 1979-, et al.
(author)
-
Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
- 2022
-
In: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
-
Journal article (peer-reviewed)abstract
- Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
|
|
| 10. |
|
|
