| 1. |
- Berndt, Sonja I., et al.
(författare)
-
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
-
Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
|
|
| 2. |
- Klevebring, Daniel, 1981-
(författare)
-
On Transcriptome Sequencing
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is about the use of massive DNA sequencing to investigate the transcriptome. During recent decades, several studies have made it clear that the transcriptome comprises a more complex set of biochemical machinery than was previously believed. The majority of the genome can be expressed as transcripts; and overlapping and antisense transcription is widespread. New technologies for the interroga- tion of nucleic acids have made it possible to investigate such cellular phenomena in much greater detail than ever before. For each application, special requirements need to be met. The work presented in this thesis focuses on the transcrip- tome and the development of technology for its analysis. In paper I, we report our development of an automated approach for sample preparation. The procedure was benchmarked against a publicly available reference data set, and we note that our approach outperformed similar manual procedures in terms of reproducibility. In the work reported in papers II-IV, we used different massive sequencing technologies to investigate the transcriptome. In paper II we describe a concatemerization approach that increased throughput by 65% using 454 sequencing,and we identify classes of transcripts not previously described in Populus. Papers III and IV both report studies based on SOLiD sequencing. In the former, we investigated transcripts and proteins for 13% of the human gene and detected a massive overlap for the upper 50% transcriptional levels. In the work described in paper IV, we investigated transcription in non-genic regions of the genome and detected expression from a high number of previ- ously unknown loci.
|
|
| 3. |
- Ameur, Adam, et al.
(författare)
-
De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data
- 2018
-
Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 9:10
-
Tidskriftsartikel (refereegranskat)abstract
- The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.
|
|
| 4. |
- Halvorsen, Matthew, et al.
(författare)
-
Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1, s. 1842-
-
Tidskriftsartikel (refereegranskat)abstract
- Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
|
|
| 5. |
- Nordin, Jessika, et al.
(författare)
-
SweHLA : the high confidence HLA typing bio-resource drawn from 1000 Swedish genomes
- 2020
-
Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 28:5, s. 627-635
-
Tidskriftsartikel (refereegranskat)abstract
- There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimizing the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1000 Swedish genomes, and a framework for future HLA interrogation. HLA 2nd-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, HLA-B, HLA-C; class II: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1). A high confidence population set (SweHLA) was determined using an n−1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and individual programs benchmarked to SweHLA. Per gene, 875 to 988 of the 1000 samples were genotyped in SweHLA; 920 samples had at least seven loci called. While a small fraction of reference alleles were common to all software (class I = 1.9% and class II = 4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations (>0.83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency >2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to individual HLA software biases.
|
|
| 6. |
- Sturk-Andreaggi, Kimberly, 1981-, et al.
(författare)
-
Mitochondrial DNA genome variation in the Swedish population
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The development of mitochondrial genome (mitogenome) reference data for inclusion in publicly-available population databases is currently underway, and the more high-quality mitogenomes that can be generated will only enhance the statistical power of this forensically-useful locus. In order to promote mitogenome testing in Sweden, the mitochondrial DNA (mtDNA) data from the SweGen whole genome sequencing (WGS) dataset were analysed. To avoid the interference from nuclear mtDNA segments (NUMTs), a 10% frequency threshold was applied for the population analyses. In total, 934 forensic-quality mitogenome haplotypes were produced. Despite the elevated frequency threshold, 31 NUMT variants were observed in 13 lower coverage haplotypes. However, NUMT interference was minimal and localized to two hotspot regions, substantially reducing the analysis burden required at lower frequency thresholds. Almost 45% of the SweGen haplotypes belonged to haplogroup H and nearly all mitogenome haplotypes (99.1%) assigned to European haplogroups, which was expected based on previous mtDNA studies of the Swedish population. There were characteristic northern Swedish (i.e., Saami) and Finnish haplogroups observe in the dataset, consistent with the nuclear DNA analyses of the SweGen data. The analysis of the complete mitogenome resulted in high haplotype diversity (0.9996) with a random match probability of 0.15%. Overall, the mitogenomes generated from the SweGen WGS data provide a mitogenome reference database for Sweden as well as contribute to the global effort to increase the availability of mitogenome reference data.
|
|
| 7. |
- Ameur, Adam, et al.
(författare)
-
SweGen : a whole-genome data resource of genetic variability in a cross-section of the Swedish population
- 2017
-
Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 25:11, s. 1253-1260
-
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.
|
|
| 8. |
- Evangelou, Evangelos, et al.
(författare)
-
Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
-
Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
|
|
| 9. |
- Gyllensten, Ulf, 1954-
(författare)
-
Biochemical genetic variation, intraspecific genetic structure and postglacial evolution of select north European vertebrate species
- 1984
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Analysis of the tempo and mode of intraspecific differentiation provides important information for understanding subspeciation, for construction of taxonomic hierarchies within a species and for management of genetic variation in natural populations.The present thesis describes the genetic structure of natural populations of willow grouse (Lagopus tagopus L.), rock ptarmigan (Lagopus mutus L.), red deer (Cervus ebaphus L.), fourhorn sculpin (Myoxocephalus quadricornis L.), and perch (Perea fluviatilis L.) in the recently (within 8.000 years) deglaciated Scandinavian region, studied by analysis of allozyme variation at multiple loci.The amount of genetic variation within these species was similar to previously reported means for each particular vertebrate group, except for the perch which has an extremely low level of genetic variation. All species, except perch, show a complex population genetic structure. The magnitude of genetic differentiation between populations indicates that the majority of population structures are of postglacial origin. Differentiation potentially indicating divergence times in excess of the timespan available for postglacial evolution was only observed between two Scandinavian red deer subspecies.In red deer and willow grouse, the distribution of genetic variability does not support the currently applied subspecies classifications. Taxonomic subspecies either show very little absolute genetic differentiation as for the red deer, or do not represent a general subdivision of the genetic variation within the species, as for the willow grouse. This discrepancy emphazises that morphological characters may fail to depict the evolutionary relationships among populations.Temporal variation in the genetic structure was found in willow grouse and fourhorn sculpin. This may reflect an unstable demographic structure due to population density changes in willow grouse, and lack of temporally stationary breeding units in fourhorn sculpin.In addition, a comparison was made of the genetic structure of marine, anadromous, and freshwater fishes from Scandinavia and North America, by a nested gene diversity analysis of published allele frequency data for biochemical loci. Large differences in the intraspecific distribution of genetic variability was found between marine and freshwater fish. Species with geographical barriers between localities have consistently higher levels of intraspecific genetic differentiation, as expected if migration is important in determining the genetic structure of populations.
|
|
| 10. |
- Johansson, Åsa, et al.
(författare)
-
Evaluation of the SNP tagging approach in an independent population sample : Array-based SNP discovery in Sami
- 2007
-
Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 122:2, s. 141-150
-
Tidskriftsartikel (refereegranskat)abstract
- Significant efforts have been made to determine the correlation structure of common SNPs in the human genome. One method has been to identify the sets of tagSNPs that capture most of the genetic variation. Here, we evaluate the transferability of tagSNPs between populations using a population sample of Sami, the indigenous people of Scandinavia. Array-based SNP discovery in a 4.4 Mb region of 28 phased copies of chromosome 21 uncovered 5,132 segregating sites, 3,188 of which had a minimum minor allele frequency (mMAF) of 0.1. Due to the population structure and consequently high LD, the number of tagSNPs needed to capture all SNP variation in Sami is much lower than that for the HapMap populations. TagSNPs identified from the HapMap data perform only slightly better in the Sami than choosing tagSNPs at random from the same set of common SNPs. Surprisingly, tagSNPs defined from the HapMap data did not perform better than selecting the same number of SNPs at random from all SNPs discovered in Sami. Nearly half (46%) of the Sami SNPs with a mMAF of 0.1 are not present in the HapMap dataset. Among sites overlapping between Sami and HapMap populations, 18% are not tagged by the European American (CEU) HapMap tagSNPs, while 43% of the SNPs that are unique to Sami are not tagged by the CEU tagSNPs. These results point to serious limitations in the transferability of common tagSNPs to capture random sequence variation, even between closely related populations, such as CEU and Sami.
|
|
