| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
- 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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| 3. |
- Kivipelto, Miia, et al.
(författare)
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World-Wide FINGERS Network : A global approach to risk reduction and prevention of dementia
- 2020
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:7, s. 1078-1094
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Tidskriftsartikel (refereegranskat)abstract
- Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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| 4. |
- Leu, Monica, et al.
(författare)
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NordicDB : a Nordic pool and portal for genome-wide control data
- 2010
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 18:12, s. 1322-1326
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Tidskriftsartikel (refereegranskat)abstract
- A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from similar to 5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW-SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries. European Journal of Human Genetics (2010) 18, 1322-1326; doi: 10.1038/ejhg.2010.112; published online 28 July 2010
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| 5. |
- Mowery, Danielle L., et al.
(författare)
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Normalizing acronyms and abbreviations to aid patient understanding of clinical texts : ShARe/CLEF eHealth Challenge 2013, Task 2
- 2016
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Ingår i: Journal of Biomedical Semantics. - : Springer Science and Business Media LLC. - 2041-1480. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: The ShARe/CLEF eHealth challenge lab aims to stimulate development of natural language processing and information retrieval technologies to aid patients in understanding their clinical reports. In clinical text, acronyms and abbreviations, also referenced as short forms, can be difficult for patients to understand. For one of three shared tasks in 2013 (Task 2), we generated a reference standard of clinical short forms normalized to the Unified Medical Language System. This reference standard can be used to improve patient understanding by linking to web sources with lay descriptions of annotated short forms or by substituting short forms with a more simplified, lay term. Methods: In this study, we evaluate 1) accuracy of participating systems' normalizing short forms compared to a majority sense baseline approach, 2) performance of participants' systems for short forms with variable majority sense distributions, and 3) report the accuracy of participating systems' normalizing shared normalized concepts between the test set and the Consumer Health Vocabulary, a vocabulary of lay medical terms. Results: The best systems submitted by the five participating teams performed with accuracies ranging from 43 to 72 %. A majority sense baseline approach achieved the second best performance. The performance of participating systems for normalizing short forms with two or more senses with low ambiguity (majority sense greater than 80 %) ranged from 52 to 78 % accuracy, with two or more senses with moderate ambiguity (majority sense between 50 and 80 %) ranged from 23 to 57 % accuracy, and with two or more senses with high ambiguity (majority sense less than 50 %) ranged from 2 to 45 % accuracy. With respect to the ShARe test set, 69 % of short form annotations contained common concept unique identifiers with the Consumer Health Vocabulary. For these 2594 possible annotations, the performance of participating systems ranged from 50 to 75 % accuracy. Conclusion: Short form normalization continues to be a challenging problem. Short form normalization systems perform with moderate to reasonable accuracies. The Consumer Health Vocabulary could enrich its knowledge base with missed concept unique identifiers from the ShARe test set to further support patient understanding of unfamiliar medical terms.
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| 6. |
- 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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