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- 2019
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Tidskriftsartikel (refereegranskat)
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- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 4. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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- Lu, Wentian, et al.
(författare)
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Relationship between employment histories and frailty trajectories in later life : evidence from the English Longitudinal Study of Ageing
- 2017
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 0143-005X .- 1470-2738. ; 71:5, s. 439-445
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Tidskriftsartikel (refereegranskat)abstract
- Background Given the acceleration of population ageing and policy changes to extend working lives, evidence is needed on the ability of older adults to work for longer. To understand more about the health impacts of work, this study examined the relationship between employment histories before retirement and trajectories of frailty thereafter. Methods The sample comprised 2765 women and 1621 men from the English Longitudinal Study of Ageing. We used gendered typologies of life-time employment and a frailty index (FI). Multilevel growth curve models were used to predict frailty trajectories by employment histories. Results Women who had a short break for family care, then did part-time work till 59 years had a lower FI after 60 years than those who undertook full-time work until 59 years. Women who were largely family carers or non-employed throughout adulthood, had higher levels of frailty at 60 years but experienced a slower decline with age. Men who worked full-time but early exited at either 49 or 60 years had a higher FI at 65 years than those who worked full-time up to 65 years. Interaction between employment histories and age indicated that men in full-time work who experienced an early exit at 49 tended to report slower declines. Conclusions For women, experiencing distinct periods throughout the lifecourse of either work or family care may be advantageous for lessening frailty risk in later life. For men, leaving paid employment before 65 years seems to be beneficial for decelerating increases in frailty thereafter. Continuous full-time work until retirement age conferred no long-term health benefits.
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- Ni, S., et al.
(författare)
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Last interglacial seasonal hydroclimate in the North Sea–Baltic Sea region
- 2023
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Ingår i: Quaternary Science Reviews. - 0277-3791 .- 1873-457X. ; 312
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Tidskriftsartikel (refereegranskat)abstract
- The Last Interglacial (LIG) experienced substantial changes in seasonal insolation compared with the present day, which may have affected the hydrography and water-mass exchange in the North Sea and Baltic Sea region. Here we investigate the effects of solar radiation and greenhouse gas (GHG) forcing on the regional climate by analyzing model simulations of the LIG (127 ka BP), pre-industrial (PI, 1850 CE), and present-day (PD, 1990 CE) climates. We also interpret the reconstructed seasonal bottom water conditions using benthic foraminifera and geochemistry data. Our simulations reveal that during the LIG, the Baltic Sea region (including the Kattegat and the Danish Straits) experienced more saline and colder bottom waters than those in the PD, in agreement with the reconstruction data. This can be attributed to lower GHG levels and enhanced water exchange of cooler, saline North Sea water into the Baltic Sea during the LIG. The thermocline was stronger during the summer months in the LIG, mainly due to the higher sea surface temperature (SST) compared to that of the PD resulting from increased summer insolation. Further, the temperature anomalies (LIG–PD) show significant inverse correlations with the precipitation–minus–evaporation (P–E) at the Baltic Sea entrance. However, the P–E balance appears to have had minimal impact on salinity changes in the North Sea, the Baltic Proper, and the open sea area. Our findings indicate that monthly surface and bottom water salinity anomalies of LIG-PI exhibit strong positive correlations with the North Atlantic Oscillation (NAO) anomalies in the Baltic entrance region. During the LIG, a more positive phase of the NAO index in autumn played a crucial role in wind-driven major inflows and led to more intensive water exchange in the North Sea–Baltic Sea region compared to the late Holocene.
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| 8. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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