| 1. |
- Ameur, Adam, et al.
(författare)
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SweGen : a whole-genome data resource of genetic variability in a cross-section of the Swedish population
- 2017
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 25:11, s. 1253-1260
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.
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| 2. |
- Ameur, Adam, et al.
(författare)
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Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain
- 2011
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Ingår i: Nature Structural & Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9993 .- 1545-9985. ; 18:12, s. 1435-1440
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptome sequencing allows for analysis of mature RNAs at base pair resolution. Here we show that RNA-seq can also be used for studying nascent RNAs undergoing transcription. We sequenced total RNA from human brain and liver and found a large fraction of reads (up to 40%) within introns. Intronic RNAs were abundant in brain tissue, particularly for genes involved in axonal growth and synaptic transmission. Moreover, we detected significant differences in intronic RNA levels between fetal and adult brains. We show that the pattern of intronic sequence read coverage is explained by nascent transcription in combination with co-transcriptional splicing. Further analysis of co-transcriptional splicing indicates a correlation between slowly removed introns and alternative splicing. Our data show that sequencing of total RNA provides unique insight into the transcriptional processes in the cell, with particular importance for normal brain development.
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| 3. |
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| 4. |
- Blomqvist, Mia E-L, et al.
(författare)
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Towards compendia of negative genetic association studies: an example for Alzheimer disease.
- 2006
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Ingår i: Human genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 119:1-2, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
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| 5. |
- Chen, Dan, et al.
(författare)
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Genome-wide Association Study of Susceptibility Loci for Cervical Cancer
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:9, s. 624-633
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Tidskriftsartikel (refereegranskat)abstract
- Background Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood. Methods We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided. Results Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6 x 10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3 x 10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9 x 10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA. Conclusions Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.
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| 6. |
- Eisfeldt, J, et al.
(författare)
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Hybrid sequencing resolves two germline ultra-complex chromosomal rearrangements consisting of 137 breakpoint junctions in a single carrier
- 2021
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Ingår i: Human genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 140:5, s. 775-790
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Tidskriftsartikel (refereegranskat)abstract
- Chromoanagenesis is a genomic event responsible for the formation of complex structural chromosomal rearrangements (CCRs). Germline chromoanagenesis is rare and the majority of reported cases are associated with an affected phenotype. Here, we report a healthy female carrying two de novo CCRs involving chromosomes 4, 19, 21 and X and chromosomes 7 and 11, respectively, with a total of 137 breakpoint junctions (BPJs). We characterized the CCRs using a hybrid-sequencing approach, combining short-read sequencing, nanopore sequencing, and optical mapping. The results were validated using multiple cytogenetic methods, including fluorescence in situ hybridization, spectral karyotyping, and Sanger sequencing. We identified 137 BPJs, which to our knowledge is the highest number of reported breakpoint junctions in germline chromoanagenesis. We also performed a statistical assessment of the positioning of the breakpoints, revealing a significant enrichment of BPJ-affecting genes (96 intragenic BPJs, 26 genes,p < 0.0001), indicating that the CCRs formed during active transcription of these genes. In addition, we find that the DNA fragments are unevenly and non-randomly distributed across the derivative chromosomes indicating a multistep process of scattering and re-joining of DNA fragments. In summary, we report a new maximum number of BPJs (137) in germline chromoanagenesis. We also show that a hybrid sequencing approach is necessary for the correct characterization of complex CCRs. Through in-depth statistical assessment, it was found that the CCRs most likely was formed through an event resembling chromoplexy—a catastrophic event caused by erroneous transcription factor binding.
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| 7. |
- Eisfeldt, Jesper, et al.
(författare)
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Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:16
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Tidskriftsartikel (refereegranskat)abstract
- Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.
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| 8. |
- Etemadikhah, Mitra, et al.
(författare)
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Transcriptome analysis of fibroblasts from schizophrenia patients reveals differential expression of schizophrenia-related genes
- 2020
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a complex neurodevelopmental disorder with high rate of morbidity and mortality. While the heritability rate is high, the precise etiology is still unknown. Although schizophrenia is a central nervous system disorder, studies using peripheral tissues have also been established to search for patient specific biomarkers and to increase understanding of schizophrenia etiology. Among all peripheral tissues, fibroblasts stand out as they are easy to obtain and culture. Furthermore, they keep genetic stability for long period and exhibit molecular similarities to cells from nervous system. Using a unique set of fibroblast samples from a genetically isolated population in northern Sweden, we performed whole transcriptome sequencing to compare differentially expressed genes in seven controls and nine patients. We found differential fibroblast expression between cases and controls for 48 genes, including eight genes previously implicated in schizophrenia or schizophrenia related pathways; HGF, PRRT2, EGR1, EGR3, C11orf87, TLR3, PLEKHH2 and PIK3CD. Weighted gene correlation network analysis identified three differentially co-expressed networks of genes significantly-associated with schizophrenia. All three modules were significantly suppressed in patients compared to control, with one module highly enriched in genes involved in synaptic plasticity, behavior and synaptic transmission. In conclusion, our results support the use of fibroblasts for identification of differentially expressed genes in schizophrenia and highlight dysregulation of synaptic networks as an important mechanism in schizophrenia.
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| 9. |
- Feuk, Lars
(författare)
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SNP based strategies to study candidate genes for Alzheimer’s disease
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is a genetically heterogeneous disease characterized by progressive cognitive decline and memory impairment. The rare familial form of AD is caused by three different genes called APP, PSEN1 and PSEN2. However, the predominant form of AD is a genetically complex disorder involving a combination of genetic factors. To date, the only risk factor identified for the complex form of AD is the APOE-epsilon 4 allele, but several susceptibility genes remain to be found. This thesis outlines different strategies to use common genetic variation, in the form of single nucleotide polymorphisms (SNPs), to examine candidate genes and candidate regions for AD. Large-scale genotyping is a prerequisite for performing complex disease studies using SNPs. The validity and accuracy of a newly developed genotyping assay called Dynamic allele specific hybridization (DASH) was therefore investigated. DASH was shown to be a robust genotyping method, and was proven to work as well or better than several other available methods. 'the method was first implemented for a candidate gene association study of a promoter polymorphism in the TNFRSF6 gene. Significant association was found between this variant and early onset AD, indicating its possible role in disease etiology. A large candidate pathway association study effort was then started testing for association between AD and 60 different SNPs. Genes were picked from four different pathways related to AD; oxidation, inflammation/apoptosis, amyloid interacting genes and a group of candidate genes previously showing significant association with AD. None of the markers showed significant disease association after correction for multiple testing. Although largely negative, these results high-lighted several methodological and study design issues related to association studies in general. The most successful approach yet in dissecting complex disease using genetic variation has been to perform high resolution linkage disequilibrium (LD) mapping of regions indicated by linkage. Several independent research groups recently reported linkage peaks for AD on chromosome 10q We choose two regions under the 10q linkage peak for LD mapping studies. The first region contained the previously associated TNFRSF6 gene, and the other region included the insulin-degrading enzyme (IDE) gene, which has been shown to be involved in clearance of amyloid-beta. LD maps were created for all pair-wise markers in the two regions to determine the genetic LD structure. Haplotypes were estimated and haplotype tagging markers were chosen for further analysis. Association analyses were performed for both single markers and haplotypes for case/control status as well as for quantitative traits related to the AD phenotype. Only weak significant signals were found for the TNFRSF6 gene. However, several significant associations were found for a large LD block including the IDE gene. The same haplotypes were always over-represented in cases compared to controls, or with more severe AD within the patient groups. These results indicate a role in AD for one of the three genes situated within the 276kb LD block including the IDE, KNSLI and HHEX genes. Further studies will now be required to identify the underlying risk alleles within the region.
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| 10. |
- Halvardson, Jonatan, et al.
(författare)
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Mutations in HECW2 are associated with intellectual disability and epilepsy
- 2016
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 53:10, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
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