| 1. |
- Green, Anna, 1973-, et al.
(författare)
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Copy number variants in familial hypercholesterolemia genes using targeted NGS, validated through optical genome mapping
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 159-159
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Objectives: Familial hypercholesterolemia (FH) is a common genetic disorder which is primarily caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. Approximately 10% of pathogenic variants in LDLR may be CNVs. Here, we combine NGS, MLPA, and Optical Genome Mapping (OGM) to investigate CNVs in LDLR.Methods: A NGS panel was designed for whole gene sequencing (8 genes) of 100 FH patients using Twist technology and Illumina platform. CNVs were detected using CNVexpo, and an in-house pipeline for base-resolved normalized coverage. Identified CNVs were validated using MLPA and OGM. Bionano Services Lab performed the OGM procedure. Purified gDNA was labeled using Direct Label and Stain DNA Labeling Kit. Saphyr chip was run aiming for 100X coverage. De novo assembly and Variant Annotation pipelines were executed on Bionano Solve v3.7. Bionano Access v1.7 was used for CNV reporting and visualization.Results: In five out of 100 samples NGS and MLPA data showed heterozygous deletions in LDLR. Three deletions, affecting different exons, was analyzed and confirmed using OGM. In two samples, OGM better defined the breakpoints as well as the size of the event, which expanded far beyond the gene of interest. In one sample, an additional CNV of SLCO1B1, a pharmaco-gene, important for transport of statins used for FH treatment was identified.Conclusion: CNVs in FH genes in FH patients could be detected using targeted NGS, which was further confirmed by MLPA and characterized using OGM.
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| 2. |
- Huyghe, Jeroen R, et al.
(författare)
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A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies
- 2011
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Ingår i: EUROPEAN JOURNAL OF HUMAN GENETICS. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 19:3, s. 347-352
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Tidskriftsartikel (refereegranskat)abstract
- The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F-ST statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F-ST was smallest for the comparison with the Russians (F-ST=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.
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| 3. |
- Huyghe, Jeroen R., et al.
(författare)
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Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami
- 2010
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 18:5, s. 569-574
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Tidskriftsartikel (refereegranskat)abstract
- The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.
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| 4. |
- Roos, Sara, 1979, et al.
(författare)
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A novel mitochondrial tRNA Arg mutation resulting in an anticodon swap in a patient with mitochondrial encephalomyopathy.
- 2013
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 21:5, s. 571-3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We report a mutation in the anticodon of the tRNA(Arg) gene (m.10437 G>A), resulting in an anticodon swap from GCU to ACU, which is the anticodon of tRNA(Trp), in a boy with mitochondrial encephalomyopathy. Enzyme histochemical analysis of muscle tissue and biochemical analysis of isolated muscle mitochondria demonstrated cytochrome c oxidase (COX) deficiency. Restriction fragment length polymorphism analysis showed that 90% of muscle and 82% of urinary epithelium mtDNA harbored the mutation. The mutation was not identified in blood, fibroblasts, hair roots, or buccal epithelial cells and it was absent in the asymptomatic mother, suggesting that it was a de novo mutation. Single-fiber PCR analysis showed that the proportion of mutated mtDNA correlated with enzyme histochemical COX deficiency. This mutation adds to the three previously described disease-causing mutations in tRNA(Arg), but it is the first mutation occurring in the anticodon of tRNA(Arg).European Journal of Human Genetics advance online publication, 11 July 2012; doi:10.1038/ejhg.2012.153.
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| 5. |
- Smeds, Patrik, et al.
(författare)
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Hydra-genetics, a modular framework for bioinformatics pipeline development
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 675-676
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Processing information from massively parallel sequencing/next-generation sequencing (NGS) data involves several steps that transform millions of rows of input data into more accessible genetic information. The combination of bioinformatics tools that extract all requested information for a particular clinical/research application, how they are tuned and the order in which they are executed constitute a bioinformatics pipeline. Software is often reused in several pipelines and regularly updated. For clinically validated NGS pipelines it may be challenging when individual components of several pipelines needs updating or when tools are replaced with new applications.Methods: The Hydra-genetics framework takes advantage of version controlled Snakemake modules. Pipeline steps are split into modules that can be configured and tested individually. The modules can be combined to build complete bioinformatics analyses, or be added to existing pipelines. All modules are subjected to extensive testing to ensure that new releases do not unexpectedly break existing pipelines or deviate from guidelines and best practices on how to write code.Results: Bioinformaticians from five Genomics Medicine Sweden centers used Hydra-genetics to develop the bioinformatics pipeline for the comprehensive solid tumor panel, GMS560. The pipeline analyses tumor DNA and/or RNA data and generates information on genetic variation including complex biomarkers such as tumor mutation burden and microsatellite instability. It is validated and in clinical use.Conclusions: The Hydra-genetics framework provides a platform for structured bioinformatics pipeline development and facilitates joint development projects involving multiple partners. It makes clinical pipeline development easier, faster and more structured.
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| 6. |
- Van Laer, Lut, et al.
(författare)
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A genome-wide association study for age-related hearing impairment in the Saami
- 2010
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Ingår i: European Journal of Human Genetics. - : BMJ Publishing Group Ltd. - 1018-4813 .- 1476-5438. ; 18:6, s. 685-693
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.
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