| 1. |
- 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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| 2. |
- Everitt, Turid, et al.
(författare)
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The Genomic Basis of Adaptation to High Elevations in Africanized Honey Bees
- 2023
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Ingår i: Genome Biology and Evolution. - : Oxford University Press. - 1759-6653 .- 1759-6653. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- A range of different genetic architectures underpin local adaptation in nature. Honey bees (Apis mellifera) in the Eastern African Mountains harbor high frequencies of two chromosomal inversions that likely govern adaptation to this high-elevation habitat. In the Americas, honey bees are hybrids of European and African ancestries and adaptation to latitudinal variation in climate correlates with the proportion of these ancestries across the genome. It is unknown which, if either, of these forms of genetic variation governs adaptation in honey bees living at high elevations in the Americas. Here, we performed whole-genome sequencing of 29 honey bees from both high- and low-elevation populations in Colombia. Analysis of genetic ancestry indicated that both populations were predominantly of African ancestry, but the East African inversions were not detected. However, individuals in the higher elevation population had significantly higher proportions of European ancestry, likely reflecting local adaptation. Several genomic regions exhibited particularly high differentiation between highland and lowland bees, containing candidate loci for local adaptation. Genes that were highly differentiated between highland and lowland populations were enriched for functions related to reproduction and sperm competition. Furthermore, variation in levels of European ancestry across the genome was correlated between populations of honey bees in the highland population and populations at higher latitudes in South America. The results are consistent with the hypothesis that adaptation to both latitude and elevation in these hybrid honey bees are mediated by variation in ancestry at many loci across the genome.
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| 3. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Mohr, Wiebke, et al.
(författare)
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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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Ingår i: Alzheimer's & Dementia. - : Alzheimer's Association. - 1552-5260 .- 1552-5279. ; 17:S7, s. e052134-
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Forskningsöversikt (refereegranskat)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.
(författare)
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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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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 84:1, s. 343-366
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Forskningsöversikt (refereegranskat)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. |
- O'Seaghdha, Conall M., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Tidskriftsartikel (refereegranskat)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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| 7. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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