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- Sandholm, Niina, et al.
(författare)
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Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:9, s. 1495-1509
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10−9; although not withstanding correction for multiple testing, p>9.3×10−9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN–RESP18, GPR158, INIP–SNX30, LSM14A and MFF; p<2.7×10−6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10−6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10−11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10−8] and negatively with tubulointerstitial fibrosis [p=2.0×10−9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10−16], and SNX30 expression correlated positively with eGFR [p=5.8×10−14] and negatively with fibrosis [p<2.0×10−16]). Conclusions/interpretation: Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (https://t1d.hugeamp.org/downloads.html; https://t2d.hugeamp.org/downloads.html; https://hugeamp.org/downloads.html). Graphical abstract: [Figure not available: see fulltext.]
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| 2. |
- Sandholm, Niina, et al.
(författare)
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The genetic landscape of renal complications in type 1 diabetes
- 2017
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673. ; 28:2, s. 557-574
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4310-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associatedvariants.Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2310-5) and the risk of type 2 diabetes (P=6.1310-4) associated with the risk of diabetic kidney disease.Wealso found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1310-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0310-6), and pentose and glucuronate interconversions (P=3.0310-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
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| 3. |
- André, Frida, et al.
(författare)
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Cognitive behavioral treatment for disordered gaming and problem gambling in adolescents : a pilot feasibility study
- 2022
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Ingår i: Upsala Journal of Medical Sciences. - 0300-9734. ; 127
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disordered gaming and problem gambling (DG/PG) are associated with a range of functional impairments as well as psychiatric comorbidity. With the proliferation of digital gaming apps aimed at children and adolescents, which involve in-game purchases, there is increasing evidence that DG/PG are on the rise in this age range. The behavior can be detected in youth presenting at school-based health clinics and community psychiatric clinics. Cognitive behavioral therapy (CBT) is one of several recommended treatments for adults, but little evidence is available for the efficacy of this approach in adolescents with DG/PG. Aim: To evaluate the acceptability and feasibility of a CBT-based intervention developed for adolescents with DG/PG, which can be delivered in routine psychiatric care facilities. Methods: Adolescents who were patients at a child and adolescent psychiatry service were screened for DG/PG. Those aged 12-17 years with pronounced symptoms were invited to participate in a 7-week CBT program called Relapse Prevention. Nine adolescents agreed to participate and five consented to repeated assessments of outcome (pre-, post-treatment, and 6-month follow-up). In addition to acceptability and satisfaction with treatment, symptoms of DG were assessed with standardized interview and self-report measures. Results: There were no dropouts from the treatment. Participants who completed treatment and all outcome assessments reported satisfaction with the treatment. The participants showed fewer symptoms of DG after treatment, and the proportion who met criteria for computer game addiction decreased from 56 to 0%. There was no reduction in the number of participants who met criteria for PG. Conclusion: This study provides preliminary evidence for the acceptability and feasibility of a CBT-based intervention for DG/PG in adolescents. Preliminary data suggest that the treatment may be effective for DG but not PG. Further studies are needed to evaluate the efficacy of this approach for both conditions.
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| 5. |
- von Hofsten, Claes, et al.
(författare)
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12-month–old infants’ perception of attention direction in static video images
- 2005
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Ingår i: Infancy. - : Wiley. - 1525-0008 .- 1532-7078. ; 8:3, s. 217-231
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Tidskriftsartikel (refereegranskat)abstract
- Twelve-month-old infants' ability to perceive gaze direction in static video images was investigated. The images showed a woman who performed attention-directing actions by looking or pointing toward 1 of 4 objects positioned in front of her (2 on each side). When the model just pointed at the objects, she looked straight ahead, and when she just looked, her hands were hidden below the tabletop. An eye movement system (TOBII) was used to register the gaze of the participants. We found that the infants clearly discriminated the gaze directions to the objects. There was no tendency to mix up the 2 object positions, located 10° apart, on the same side of the model. The infants spent more time looking at the attended objects than the unattended ones and they shifted gaze more often from the face of the model to the attended object than to the unattended objects. Pointing did not significantly increase the infants' tendency to move gaze to the attended object, irrespective of whether the pointing gesture was accompanied by looking or not. In all conditions the infants spent most of the time looking at the model's face. This tendency was especially noticeable in the pointing-only condition and the condition where the model just looked straight ahead.
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