| 1. |
- Shungin, Dmitry, et al.
(author)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Journal article (peer-reviewed)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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| 2. |
- Hibar, Derrek P., et al.
(author)
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Novel genetic loci associated with hippocampal volume
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 3. |
- Krüger, Nadine, et al.
(author)
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The upper respiratory tract of felids is highly susceptible to sars‐cov‐2 infection
- 2021
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:19
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Journal article (peer-reviewed)abstract
- Natural or experimental infection of domestic cats and virus transmission from humans to captive predatory cats suggest that felids are highly susceptible to SARS‐CoV‐2 infection. However, it is unclear which cells and compartments of the respiratory tract are infected. To address this question, primary cell cultures derived from the nose, trachea, and lungs of cat and lion were inoculated with SARS‐CoV‐2. Strong viral replication was observed for nasal mucosa explants and tracheal air–liquid interface cultures, whereas replication in lung slices was less efficient. Infection was mainly restricted to epithelial cells and did not cause major pathological changes. Detection of high ACE2 levels in the nose and trachea but not lung further suggests that susceptibility of feline tissues to SARS‐CoV‐2 correlates with ACE2 expression. Collectively, this study demonstrates that SARS‐ CoV‐2 can efficiently replicate in the feline upper respiratory tract ex vivo and thus highlights the risk of SARS‐CoV‐2 spillover from humans to felids.
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| 4. |
- Mohr, Wiebke, et al.
(author)
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Key components of person-centered care for people with dementia : A systematic review of interventions to design a patient preference study
- 2021
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In: Alzheimer's & Dementia. - : Alzheimer's Association. - 1552-5260 .- 1552-5279. ; 17:S7, s. e052134-
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Research review (peer-reviewed)abstract
- BACKGROUND: To provide Person-Centered Care (PCC) for People with Dementia (PwD), patient's stated preferences must be known. Data about stated care-preferences among PwD are limited. This study aimed to identify key components of PCC for PwD by a systematic review of PCC-interventions, to inform the construction of a decision model for PwD-preference elicitation.METHOD: A protocol was registered with PROSPERO (CRD42021225084). A search of the concepts Dementia, Person-Centered Care, and Intervention was performed in PubMed, EMBASE, and Web of Science in Nov2020. Study selection was based on 2-stage screening against eligibility criteria, limited to randomized controlled trials (RCT) and nonrandomized controlled study (NRS) designs. Risk of bias was assessed with version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB2) and the Newcastle-Ottawa Scale (NOS) for nonrandomized studies. Information about authors, interventions, and outcomes were extracted and entered into an "Effects Table". The identified PCC-interventions were thus synthesized into intervention categories to form key components of PCC.RESULT: Searches identified 1781 records. 19 studies (15 RCT, 4 NRS) were included after screening. The quality of the studies varied between low to moderate. The individual interventions covered a wide range of non-pharmacological, psychosocial offers, oftentimes bundled in multi-component intervention-sets. Nine intervention categories, i.e. key components of PCC to inform the construction of a decision model for PwD-preference elicitation, emerged from data synthesis: sensory enhancement/relaxation, social contact, cognitive training, validation and reminiscence, physical activities, environmental adjustments, caregiver training and support, care organization and daily living assistance. Effect measures included i.a. agitation, quality of life, antipsychotic use, depression, neuropsychiatric symptoms and behavior, with mixed results concerning the effect of the PCC interventions. All studies were conducted in nursery home or hospital settings.CONCLUSION: Nine intervention categories as key components of PCC to inform the construction of a decision model for PwD-preference elicitation could be identified. As the findings were limited to nursery home and hospital settings, community-dwelling PwD and the primary care-setting should find greater consideration for future investigations on PCC interventions and patient preference studies.
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| 5. |
- Mohr, Wiebke, et al.
(author)
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Key Intervention Categories to Provide Person-Centered Dementia Care : A Systematic Review of Person-Centered Interventions
- 2021
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 84:1, s. 343-366
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Research review (peer-reviewed)abstract
- Background: Person-centered care (PCC) is an important concept in many countries' national guidelines and dementia plans. Key intervention categories, i.e., a taxonomy of person-centered (PC)-interventions, to provide person-centered dementia care, are difficult to identify from literature.Objective: This systematic review aimed to identify and categorize published PC-interventions into key intervention categories to guide the provision of person-centered dementia care.Methods: Conduct of this systematic review followed Cochrane guidelines. A search of the dimensions 'Dementia', 'Person-Centered Care', and 'Intervention' combined was performed in PubMed, EMBASE, and Web of Science. Study selection was based on 2-stage screening against eligibility criteria, limited to controlled study designs. Information about interventions and outcomes was extracted into an 'Effects Table'. The identified PC-interventions were categorized in intervention categories to provide person-centered dementia care.Results: Searches identified 1,806 records. 19 studies were included. These covered a range of psychosocial interventions, oftentimes multi-component interventions, which followed heterogeneous approaches. Studies were conducted in long-term care/hospital settings. Nine key intervention categories were identified: social contact, physical activities, cognitive training, sensory enhancement, daily living assistance, life history oriented emotional support, training and support for professional caregivers, environmental adjustments, and care organization.Conclusion: Our findings provide a current overview of published PC-interventions in dementia, which followed heterogeneous approaches under the PCC-concept. The heterogeneity made it challenging to identify a well-defined concept of PCC and common key intervention categories. An effectiveness-evaluation of 'PC' - including 'relationship-centered'-interventions may be valuable, to assess whether an explicit focus on relationships around PCC-interventions yields an added benefit.PROSPERO-ID: CRD42021225084.
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| 6. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 7. |
- Stitziel, Nathan O., et al.
(author)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
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Journal article (peer-reviewed)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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| 8. |
- Webb, Thomas R., et al.
(author)
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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
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Journal article (peer-reviewed)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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