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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 4. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 5. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 6. |
- Aazh, Hashir, et al.
(författare)
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Insights from the Third International Conference on Hyperacusis : Causes, Evaluation, Diagnosis, and Treatment
- 2018
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Ingår i: Noise & Health. - : Wolters Kluwer. - 1463-1741 .- 1998-4030. ; 20:95, s. 162-170
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hyperacusis is intolerance of certain everyday sounds that causes significant distress and impairment in social, occupational, recreational, and other day-to-day activities. Objective: The aim of this report is to summarize the key findings and conclusions from the Third International Conference on Hyperacusis.Topics covered: The main topics discussed comprise (1) diagnosis of hyperacusis and audiological evaluations, (2) neurobiological aspect of hyperacusis, (3) misophonia, (4) hyperacusis in autism spectrum disorder, (5) noise sensitivity, (6) hyperacusis-related distress and comorbid psychiatric illness, and (7) audiologist-delivered cognitive behavioral therapy for hyperacusis.Conclusions: Implications for research and clinical practice are summarised.
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| 8. |
- Manchaiah, Vinaya K. C., 1983-, et al.
(författare)
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The genetic basis of auditory neuropathy spectrum disorder (ANSD)
- 2011
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Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier. - 0165-5876 .- 1872-8464. ; 75:2, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder which can have either congenital or acquired causes. Furthermore, the aetiology of auditory neuropathy is vast, which may include prematurity, hyperbilirubinaemia, anoxia, hypoxia, congenital brain anomalies, ototoxic drug exposure, and genetic factors. It is estimated that approximately 40% of cases have an underlying genetic basis, which can be inherited in both syndromic and non syndromic conditions. This review paper provides an overview of the genetic conditions associated with auditory neuropathy spectrum disorders (ANSDs) and highlights some of the defective genes that have been found to be linked to the pathological auditory changes.Method: Literature search was conducted using a number of resources including textbooks, professional journals and the relevant websites. Results: The largest proportion of auditory neuropathy spectrum disorders (ANSDs) is due to genetic factors which can be syndromic, non-syndromic or mitochondrial related. The inheritance pattern can include all the four main types of inheritances such as autosomal dominant, autosomal recessive, X-linked and mitochondrial. Conclusion: This paper has provided an overview of mutation with some of the genes and/or loci discovered to be the cause for auditory neuropathy spectrum disorders (ANSDs). It has been noted that different gene mutations may trigger different pathological changes in patients with this disorder. These discoveries have provided us with vital information as to the sites of pathology in auditory neuropathy spectrum disorders (ANSDs), and the results highlight the heterogeneity of the disorder.
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