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- Bolin, Karin, 1982-, et al.
(författare)
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Variants in BANK1 are associated with lupus nephritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lupus nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN.Methods: The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN, proliferative nephritis, end-stage renal disease and LN negative patients. SNPs with p-value <0.001 in the discovery cohort were analyzed in replication cohort 1. Ten SNPs associated with LN in the discovery cohort (p<0.0002) were genotyped in replication cohort 2. DNA methylation data were available for 180 LN patients from the discovery cohort.Results: In the discovery cohort, six gene loci were associated with LN (p<1x10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y and PHCA). SNPs in BANK1 showed the strongest association with LN in replication cohort 1 (p=9.5x10-4), with a tendency for an association in replication cohort 2 (p=0.052). In a meta-analysis of all three cohorts the association between LN and BANK1 rs4699259, was strengthened (p=1.7x10‑7). There were no associations to proliferative nephritis or ESRD in the meta-analysis. Methylation quantitative trait loci (MeQTL) effects between a CpG site and several SNPs in BANK1 were identified.Conclusion: Genetic variations in BANK1 are associated with LN. There is evidence for genetic regulation of DNA methylation within the BANK1 locus, however, the exact role of BANK1 in LN pathogenesis remains to be elucidated.
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- Dahlberg, Johan, 1988-
(författare)
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Genetic Cartography at Massively Parallel Scale
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Massively parallel sequencing (MPS) is revolutionizing genomics. In this work we use, refine, and develop new tools for the discipline.MPS has led to the discovery of multiple novel subtypes in Acute Lymphoblastic Leukemia (ALL). In Study I we screen for fusion genes in 134 pediatric ALL patients, including patients without an assigned subtype. In approximately 80% of these patients we detect novel or known fusion gene families, most of which display distinct methylation and expression patterns. This shows the potential for improvements in the clinical stratification of ALL. Large sample sizes are important to detect recurrent somatic variation. In Study II we investigate if a non-index overlapping pooling schema can be used to increase sample size and detect somatic variation. We designed a schema for 172 ALL samples and show that it is possible to use this method to call somatic variants.Around the globe there are many ongoing and completed genome projects. In Study III we sequenced the genome of 1000 Swedes to create a reference data set for the Swedish population. We identified more than 10 million variants that were not present in publicly available databases, highlighting the need for population-specific resources. Data, and the tools developed during this study, have been made publicly available as a resource for genomics in Sweden and abroad.The increased amount of sequencing data has created a greater need for automation. In Study IV we present Arteria, a computational automation system for sequencing core facilities. This system has been adopted by multiple facilities and has been used to analyze thousands of samples. In Study V we developed CheckQC, a program that provides automated quality control of Illumina sequencing runs. These tools make scaling up MPS less labour intensive, a key to unlocking the full future potential of genomics.The tools, and data presented here are a valuable contribution to the scientific community. Collectively they showcase the power of MPS and genomics to bring about new knowledge of human health and disease.
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- Marincevic-Zuniga, Yanara, 1987-
(författare)
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Resolving the Genomic Complexity of Pediatric Acute Lymphoblastic Leukemia
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the Nordic countries. Structural chromosomal rearrangements are a hallmark of ALL and represent key markers for diagnosis, risk stratification and prognosis. Nevertheless, a substantial proportion of ALL cases (~25%) lack known risk-stratifying markers and are commonly referred to as the B-other subgroup. Improved delineation of structural alterations within this subgroup could provide additional information for diagnosis, prognosis and treatment decisions. Therefore, the aim of this thesis was to decipher the genetic alterations in pediatric ALL, focusing on patients in the B-other subgroup that lack known risk-stratifying markers, and to gain further understanding of the prognostic relevance of aberrant chromosomal changes in ALL.This thesis comprises four studies. In study I we identified a novel and recurrent fusion gene (PAX5-ESRRB) in four B-other patients using a combination of RNA-sequencing and copy number analysis. These patients displayed a distinct gene expression and DNA-methylation pattern that differed from other subtypes of ALL. In study II we further explored the fusion gene landscape in ALL by applying RNA-sequencing to 134 patient samples assigned to different subtypes, including the B-other subgroup. We detected several novel and recurrent fusion gene families in approximately 80% of the B-other patients of which several were associated with distinct DNA methylation and gene expression profiles. Following on from study II, in study III we utilized subtype-specific DNA methylation patterns to design DNA methylation-based classifiers to screen for subtype membership in ~1100 ALL samples including a large group of B-other samples (25%). Re-classification of B-other samples into a new subtype using DNA methylation as the sole marker for subtype classification was validated by RNA-sequencing, which identified previously unknown fusion genes. In study IV, “linked-read” whole genome sequencing was applied to 13 ALL samples for in-depth analysis of chromosomal rearrangements. We detected all known pathogenic variants with this technique and also identified previously unknown structural aberrations at a resolution beyond that obtained by traditional karyotyping.Together, these studies provide novel insights into the structural variation present in ALL and their potential clinical relevance, which may contribute to improved treatment stratification and risk-evaluation of children diagnosed with ALL in the future.
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- Reid, Sarah, et al.
(författare)
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From genetic predisposition to clinical outcome in systemic lupus erythematosus : construction and validation of sub-phenotype-specific genetic risk scores
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectiveThis study aimed to link known genetic risk factors for systemic lupus erythematosus (SLE) with specific clinical manifestations of the disease, in both a large biobank population and in a clinical cohort of patients with SLE.MethodsScandinavian patients with SLE (n=1487) who fulfilled ≥4 ACR-82/ACR-97/SLICC-2012 classification criteria, were genotyped using the Immunochip or Global Screening array (Illumina). Clinical data was collected from medical records. Summary statistics for 57 established SLE risk SNPs (p<5×10-8 in the European population) with a validated cumulative effect on disease severity in SLE, was retrieved for 30 FinnGen datasets covering manifestations relevant for SLE. Mendelian randomization (MR) analysis was performed using the inverse variance weighed method. Nine datasets were selected for construction of standardized genetic risk scores (GRSs), which were validated in the clinical cohort using gender- and disease duration-adjusted logistic regression.ResultsIn the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14)) and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, the GRSs generated from the FinnGen datasets were associated with their corresponding manifestation for arthritis, OR 1.15 (1.02– 1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56).ConclusionBy considering associations of SLE risk SNPs with SLE-like manifestations in the FinnGen biobank, construction and validation of GRSs for five of the eleven ACR-82 criteria was possible. The findings may facilitate personalized risk prediction and targeted intervention strategies for patients with SLE.
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