| 1. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 2. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 3. |
- Asselbergs, Folkert W., et al.
(författare)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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| 4. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- ODonnell, Michael, et al.
(författare)
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Registered Replication Report: Dijksterhuis and van Knippenberg (1998)
- 2018
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Ingår i: Perspectives on Psychological Science. - : SAGE PUBLICATIONS LTD. - 1745-6916 .- 1745-6924. ; 13:2, s. 268-294
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Tidskriftsartikel (refereegranskat)abstract
- Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (professor) subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence (soccer hooligans). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%-3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and -0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the professor category and those primed with the hooligan category (0.14%) and no moderation by gender.
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| 6. |
- Tragante, Vinicius, et al.
(författare)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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| 7. |
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| 8. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 9. |
- Batlokwa, Bareki Shima, et al.
(författare)
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A Novel Molecularly Imprinted Polymer for the Selective Removal of Chlorophyll from Heavily Pigmented Green Plant Extracts prior to Instrumental Analysis
- 2013
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Ingår i: Journal of Chemistry. - : Hindawi Limited. - 2090-9071 .- 2090-9063.
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Tidskriftsartikel (refereegranskat)abstract
- A novel molecularly imprinted polymer (MIP) powder designed for the selective removal of interfering chlorophyll pigment from heavily pigmented green plant extracts during pesticide residue analysis or analysis for bioactives in natural product research is reported. The polymer powder imprinted with chlorophyll.. was synthesized by copolymerizing the functional and cross-linking monomers, methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA), respectively. During batch rebinding experiments, the MIP effectively removed chlorophyll from neat chlorophyll standards, green medicinal plants, and spinach extracts with determined absorbance as high as 2.501 absorbance units (Au) to as low as 0.084 Au after the optimum quantity of the MIP (170 mg mL(-1)) was added as the adsorbent prior to instrumental analysis. The determined 0.084 Au absorbance was far below the absorbance of 2% chlorophyll (0.401 Au) regarded as the cut-off point for interfering chlorophyll. Thus the newly developed polymer presents itself as a suitable adsorbent for the selective removal of chlorophyll from heavily pigmented, chlorophyll containing extracts.
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| 10. |
- Carlson, Allan D., et al.
(författare)
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Results of a New Evaluation of the Neutron Standards
- 2018
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Ingår i: Reactor Dosimetry. - : ASTM International. - 9780803176614 ; , s. 91-104
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Konferensbidrag (refereegranskat)abstract
- An international effort has produced evaluations of the neutron data standards. Evaluations were obtained for the cross section standards: the H(n,n), 6Li(n,t), 10B(n,067), loB(vx), natc(n,n,) Au(n,y), 235U(n,f), and 238U(n,f) reactions. Also in the evaluation process, the 238U(n,y) and 239Pu(n,f) nonstandard cross sections were evaluated. Many of these are dosimetry cross sections. Evaluations were also obtained for data that are not traditional standards: Maxwellian spectrum averaged cross section for the Au(n,y) cross section at 30 keV, reference cross sections for prompt y-ray production in fast neutron-induced reactions, reference cross sections for very high-energy fission cross sections, the 252Cf spontaneous fission neutron spectrum and the 235U thermal fission neutron spectrum, and the thermal constants. The data and covariances were obtained directly from this evaluation procedure as is required by the dosimetry community.
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| 11. |
- Carstens, Adam, 1975-, et al.
(författare)
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The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis
- 2019
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Ingår i: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD.METHODS: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified.RESULTS: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD.DISCUSSION: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.
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| 12. |
- Corriveau-Lecavalier, Nick, et al.
(författare)
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Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome
- 2024
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Ingår i: BRAIN COMMUNICATIONS. - 2632-1297. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials. Corriveau-Lecavalier et al. propose clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome, which refers to a neurologic syndrome of a slow and predominant amnestic syndrome localizing to the degeneration of the limbic system. Limbic-predominant amnestic neurodegenerative syndrome is agnostic to molecular pathology, although highly associated with transactive response DNA-binding protein 43.
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| 13. |
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| 14. |
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| 15. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 16. |
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| 17. |
- Heyne, Henrike O, et al.
(författare)
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Genetic influences on brain gene expression in rats selected for tameness and aggression.
- 2014
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 198:3
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for >64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals.
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| 18. |
- Johansson, Anna Maria, et al.
(författare)
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Characterization of genetic diversity and gene mapping in two Swedish local chicken breeds
- 2015
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this paper is to study genetic diversity in the two Swedish local chicken breeds Bohuslän-Dals svarthöna and Hedemorahöna. The now living birds of both of these breeds (about 500 for Bohuslän-Dals svarthöna and 2600 for Hedemorahöna) originate from small relicts of earlier larger populations. An additional aim was to make an attempt to map loci associated with a trait that are segregating in both these breeds. The 60k SNP chip was used to genotype 12 Bohuslän-Dals svarthöna and 22 Hedemorahöna. The mean inbreeding coefficient was considerably larger in the samples from Hedemorahöna than in the samples from Bohuslän-Dals svarthöna. Also the proportion of homozygous SNPs in individuals was larger in Hedemorahöna. In contrast, on the breed level, the number of segregating SNPs were much larger in Hedemorahöna than in Bohuslän-Dals svarthöna. A multidimensional scaling plot shows that the two breeds form clusters well-separated from each other. Both these breeds segregate for the dermal hyperpigmentation phenotype. In Bohuslän-Dals svarthöna most animals have dark skin, but some individuals with lighter skin exists (most easily detected by their red comb). An earlier study of the Fm locus showed that this breed has the same complex rearrangement involving the EDN3 gene as Silkie chicken and two other studied Asian breeds. In the breed Hedemorahöna, most individuals have normal skin pigmentation (and red comb), but there are some birds with darker skin and dark comb. In this study the involvement of the EDN3 gene is confirmed also in Hedemorahöna. In addition we identify a region on chromosome 21 that is significantly associated with the trait.
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| 19. |
- Knopman, David S., et al.
(författare)
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The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease : Perspectives from the Research Roundtable
- 2018
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:4, s. 563-575
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Forskningsöversikt (refereegranskat)abstract
- The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.
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| 20. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 21. |
- Nakiganda, Lydia Jacenta, et al.
(författare)
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Cross-sectional comparative study of risky sexual behaviours among HIV-infected persons initiated and waiting to start antiretroviral therapy in rural Rakai, Uganda
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To compare risky sexual behaviours between HIV-positive persons initiated on antiretroviral therapy (ART) (ART-experienced) and persons waiting to start on ART (ART-naive) and assess predictors of risky sexual behaviours among HIV-infected patients in rural Rakai district, Uganda. Study design This is a cross-sectional study that used data from the Rakai Community Cohort Study (RCCS) database between 2013 and 2014. A structured questionnaire was used for data collection. We used stepwise logistic regression as an index to estimate the adjusted ORs for the association between risky sexual behaviours and ART treatment status. Study setting This study was conducted in Rakai district, located in south-western Uganda. The data for this study were extracted from the RCCS. RCCS is an open prospective cohort of approximately 15 000 consenting participants aged 15-49 years. Participants HIV-positive participants aged 18-49 years who had sex at least once a month with any partner prior to the start of the study. Main outcome measures Inconsistent/no condom use in the last 12 months, alcohol use at last sexual encounter, and two or more sexual partners. Results ART-naive participants were more likely to report inconsistent condom use (OR=1.74, 95% CI 1.11 to 2.73) and more likely to drink alcohol at last sexual encounter (OR=1.65, 95% CI 1.11 to 2.46), compared with ART-experienced patients. ART treatment status (p<0.001) was a significant predictor of risky sexual behaviours. Both marital status (p=0.016) and occupation level (p=0.009) were positively associated with inconsistent condom use, while sex (p<0.001) correlated with alcohol use at last sexual encounter. Conclusion ART-naive participants were more likely to exhibit risky sexual behaviours than the ART-experienced participants. The intensity of risk reduction counselling should be increased for HIV-positive persons waiting to start ART but already in HIV care.
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| 22. |
- Nelson, Ronald, et al.
(författare)
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A century after Fisher : time for a new paradigm in quantitative genetics.
- 2013
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Ingår i: Trends in Genetics. - : Elsevier BV. - 0168-9525 .- 1362-4555. ; 29:12
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative genetics traces its roots back through more than a century of theory, largely formed in the absence of directly observable genotype data, and has remained essentially unchanged for decades. By contrast, molecular genetics arose from direct observations and is currently undergoing rapid changes, making the amount of available data ever greater. Thus, the two disciplines are disparate both in their origins and their current states, yet they address the same fundamental question: how does the genotype affect the phenotype? The rapidly accumulating genomic data necessitate sophisticated analysis, but many of the current tools are adaptations of methods designed during the early days of quantitative genetics. We argue here that the present analysis paradigm in quantitative genetics is at its limits in regards to unraveling complex traits and it is necessary to re-evaluate the direction that genetic research is taking for the field to realize its full potential.
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| 23. |
- Nelson, Ronald, et al.
(författare)
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Degrees of separation as a statistical tool for evaluating candidate genes
- 2014
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Ingår i: Computers in Biology and Medicine. - : Elsevier BV. - 0010-4825 .- 1879-0534. ; 55, s. 49-52
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Tidskriftsartikel (refereegranskat)abstract
- Selection of candidate genes is an important step in the exploration of complex genetic architecture. The number of gene networks available is increasing and these can provide information to help with candidate gene selection. It is currently common to use the degree of connectedness in gene networks as validation in Genome Wide Association (GWA) and Quantitative Trait Locus (QTL) mapping studies. However, it can cause misleading results if not validated properly. Here we present a method and tool for validating the gene pairs from GWA studies given the context of the network they co-occur in. It ensures that proposed interactions and gene associations are not statistical artefacts inherent to the specific gene network architecture. The CandidateBacon package provides an easy and efficient method to calculate the average degree of separation (DoS) between pairs of genes to currently available gene networks. We show how these empirical estimates of average connectedness are used to validate candidate gene pairs. Validation of interacting genes by comparing their connectedness with the average connectedness in the gene network will provide support for said interactions by utilising the growing amount of gene network information available. (C) 2014 Elsevier Ltd. All rights reserved.
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| 24. |
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| 25. |
- Nelson, Ronald, et al.
(författare)
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Genetics of Interactive Behavior in Silver Foxes (Vulpes vulpes)
- 2017
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Ingår i: Behavior Genetics. - : Springer Science and Business Media LLC. - 0001-8244 .- 1573-3297. ; 47:1, s. 88-101
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Tidskriftsartikel (refereegranskat)abstract
- Individuals involved in a social interaction exhibit different behavioral traits that, in combination, form the individual's behavioral responses. Selectively bred strains of silver foxes (Vulpes vulpes) demonstrate markedly different behaviors in their response to humans. To identify the genetic basis of these behavioral differences we constructed a large F2 population including 537 individuals by cross-breeding tame and aggressive fox strains. 98 fox behavioral traits were recorded during social interaction with a human experimenter in a standard four-step test. Patterns of fox behaviors during the test were evaluated using principal component (PC) analysis. Genetic mapping identified eight unique significant and suggestive QTL. Mapping results for the PC phenotypes from different test steps showed little overlap suggesting that different QTL are involved in regulation of behaviors exhibited in different behavioral contexts. Many individual behavioral traits mapped to the same genomic regions as PC phenotypes. This provides additional information about specific behaviors regulated by these loci. Further, three pairs of epistatic loci were also identified for PC phenotypes suggesting more complex genetic architecture of the behavioral differences between the two strains than what has previously been observed.
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| 26. |
- Nelson, Ronald, et al.
(författare)
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Higher order interactions : detection of epistasis using machine learning and evolutionary computation.
- 2013
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Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1064-3745 .- 1940-6029. ; 1019:1019, s. 499-518
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Tidskriftsartikel (refereegranskat)abstract
- Higher order interactions are known to affect many different phenotypic traits. The advent of large-scale genotyping has, however, shown that finding interactions is not a trivial task. Classical genome-wide association studies (GWAS) are a useful starting point for unraveling the genetic architecture of a phenotypic trait. However, to move beyond the additive model we need new analysis tools specifically developed to deal with high-dimensional genotypic data. Here we show that evolutionary algorithms are a useful tool in high-dimensional analyses designed to identify gene-gene interactions in current large-scale genotypic data.
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| 27. |
- Nelson, Ronald M., et al.
(författare)
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Genomewide analysis of admixture and adaptation in the Africanized honeybee
- 2017
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Ingår i: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 26:14, s. 3603-3617
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Tidskriftsartikel (refereegranskat)abstract
- Genetic exchange by hybridization or admixture can make an important contribution to evolution, and introgression of favourable alleles can facilitate adaptation to new environments. A small number of honeybees (Apis mellifera) with African ancestry were introduced to Brazil similar to 60 years ago, which dispersed and hybridized with existing managed populations of European origin, quickly spreading across much of the Americas in an example of a massive biological invasion. Here, we analyse whole-genome sequences of 32 Africanized honeybees sampled from throughout Brazil to study the effect of this process on genome diversity. By comparison with ancestral populations from Europe and Africa, we infer that these samples have 84% African ancestry, with the remainder from western European populations. However, this proportion varies across the genome and we identify signals of positive selection in regions with high European ancestry proportions. These observations are largely driven by one large gene-rich 1.4-Mbp segment on chromosome 11 where European haplotypes are present at a significantly elevated frequency and likely confer an adaptive advantage in the Africanized honeybee population. This region has previously been implicated in reproductive traits and foraging behaviour in worker bees. Finally, by analysing the distribution of ancestry tract lengths in the context of the known time of the admixture event, we are able to infer an average generation time of 2.0 years. Our analysis highlights the processes by which populations of mixed genetic ancestry form and adapt to new environments.
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| 28. |
- Nelson, Ronald, et al.
(författare)
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MAPfastR : Quantitative trait loci mapping in outbred line crosses
- 2013
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Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 3, s. 2147-2149
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Tidskriftsartikel (refereegranskat)abstract
- MAPfastR is a software package developed to analyze quantitative trait loci data from inbred and outbred line-crosses. The package includes a number of modules for fast and accurate quantitative trait loci analyses. It has been developed in the R language for fast and comprehensive analyses of large datasets. MAPfastR is freely available at: http://www.computationalgenetics.se/?page_id=7
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| 29. |
- Nelson, Ronald, et al.
(författare)
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qtl.outbred: Interfacing outbred line cross data with the R/qtl mapping software
- 2011
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Ingår i: BMC Research Notes. - : BioMed Central. - 1756-0500. ; 4:154
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Tidskriftsartikel (refereegranskat)abstract
- Backgroundqtl.outbred is an extendible interface in the statistical environment, R, for combining quantitative trait loci (QTL) mapping tools. It is built as an umbrella package that enables outbred genotype probabilities to be calculated and/or imported into the software package R/qtl.FindingsUsing qtl.outbred, the genotype probabilities from outbred line cross data can be calculated by interfacing with a new and efficient algorithm developed for analyzing arbitrarily large datasets (included in the package) or imported from other sources such as the web-based tool, GridQTL.Conclusionqtl.outbred will improve the speed for calculating probabilities and the ability to analyse large future datasets. This package enables the user to analyse outbred line cross data accurately, but with similar effort than inbred line cross data.
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| 30. |
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| 31. |
- Nelson, Ronald, et al.
(författare)
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Variance heterogeneity in Saccharomyces cerevisiae expression data : trans-regulation and epistasis.
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results from the first variance heterogeneity Genome Wide Association Study (VGWAS) on yeast expression data. Using this forward genetics approach, we show that the genetic regulation of gene-expression in the budding yeast, Saccharomyces cerevisiae, includes mechanisms that can lead to variance heterogeneity in the expression between genotypes. Additionally, we performed a mean effect association study (GWAS). Comparing the mean and variance heterogeneity analyses, we find that the mean expression level is under genetic regulation from a larger absolute number of loci but that a higher proportion of the variance controlling loci were trans-regulated. Both mean and variance regulating loci cluster in regulatory hotspots that affect a large number of phenotypes; a single variance-controlling locus, mapping close to DIA2, was found to be involved in more than 10% of the significant associations. It has been suggested in the literature that variance-heterogeneity between the genotypes might be due to genetic interactions. We therefore screened the multi-locus genotype-phenotype maps for several traits where multiple associations were found, for indications of epistasis. Several examples of two and three locus genetic interactions were found to involve variance-controlling loci, with reports from the literature corroborating the functional connections between the loci. By using a new analytical approach to re-analyze a powerful existing dataset, we are thus able to both provide novel insights to the genetic mechanisms involved in the regulation of gene-expression in budding yeast and experimentally validate epistasis as an important mechanism underlying genetic variance-heterogeneity between genotypes.
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| 32. |
- Pettersson, Mats, et al.
(författare)
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Selection on variance-controlling genes : adaptability or stability.
- 2012
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Ingår i: Evolution. - : Wiley. - 0014-3820 .- 1558-5646. ; 66:12
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Tidskriftsartikel (refereegranskat)abstract
- Simulations on a model system where a variance-controlling master locus scales the effects of a set of effector loci show that selection affects the variance-controlling locus more strongly than the effector loci, and that the direction of selection is dependent on the frequency of environmental changes.
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| 33. |
- Rosser, Neil, et al.
(författare)
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Hybrid speciation driven by multilocus introgression of ecological traits
- 2024
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Ingår i: Nature. - 0028-0836. ; 628, s. 811-817
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Tidskriftsartikel (refereegranskat)abstract
- Hybridization allows adaptations to be shared among lineages and may trigger the evolution of new species1,2. However, convincing examples of homoploid hybrid speciation remain rare because it is challenging to demonstrate that hybridization was crucial in generating reproductive isolation3. Here we combine population genomic analysis with quantitative trait locus mapping of species-specific traits to examine a case of hybrid speciation in Heliconius butterflies. We show that Heliconius elevatus is a hybrid species that is sympatric with both parents and has persisted as an independently evolving lineage for at least 180,000 years. This is despite pervasive and ongoing gene flow with one parent, Heliconius pardalinus, which homogenizes 99% of their genomes. The remaining 1% introgressed from the other parent, Heliconius melpomene, and is scattered widely across the H. elevatus genome in islands of divergence from H. pardalinus. These islands contain multiple traits that are under disruptive selection, including colour pattern, wing shape, host plant preference, sex pheromones and mate choice. Collectively, these traits place H. elevatus on its own adaptive peak and permit coexistence with both parents. Our results show that speciation was driven by introgression of ecological traits, and that speciation with gene flow is possible with a multilocus genetic architecture.
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| 34. |
- 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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| 35. |
- Teslovich, Tanya M., et al.
(författare)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 36. |
- Twongyirwe, Ronald, et al.
(författare)
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Projected land use change in an oil-rich landscape in Uganda : A participatory modelling approach
- 2022
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Ingår i: The Extractive Industries and Society. - : Elsevier. - 2214-790X .- 2214-7918. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of oil in the North Albertine Rift Landscape of Uganda has increased pressure on land andheightened the potential for resource use conflict. In this article, we focus on changing land use dynamics as oilextraction unfolds in a new resource frontier. We ask how the development of the nascent oil industry will affectland use dynamics, including land use conflicts. This leads us to identify the land use change already arising andto use this as the basis for participatory modelling of projected change. Given they are dominant forms of landuse, agriculture and forestry are central to our analysis. Design of the methodology combined remote sensingwith innovative modelling incorporating participatory development methods. This facilitated insight into projected land use patterns, and specifically relationships between small-scale food production, commercial sugarcane production, and forestry conservation adjacent to settlement areas. Our data show that ill–defined landboundaries and an aggressive sugarcane out-grower scheme are avenues for so-called land grabbing. Modellingscenarios under both the status quo and under oil extraction suggest the land area covered by sugarcane production will increase at the expense of food crop farming. Given a context where forestry conservation is animportant form of land use, we also consider the implications of local agricultural change on land reserved forconservation. Overall, our modelling indicates that in accounting for land use change within the resource frontierassociated with oil extraction, there needs to be insight into the intricate interconnections between differentforms of rural land use as future change unfolds. Understanding how oil extraction effects rural land use patternsholds relevance for planning in contexts of the Global South where new oil industries are emerging. Innovativemethodologies for teasing out these complex land use dynamics can aid planning that seeks to anticipate andreduce land use conflict and support agricultural livelihoods.
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| 37. |
- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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