ORCID Profile
0000-0003-3394-6495
Current Organisation
Uppsala University
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Publisher: Wiley
Date: 02-11-2016
DOI: 10.1111/JOIM.12569
Abstract: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10 Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
Publisher: BMJ
Date: 09-10-2020
DOI: 10.1136/ANNRHEUMDIS-2020-218636
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular ersity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy in iduals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in in idual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
Publisher: Oxford University Press (OUP)
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 15-08-2023
DOI: 10.1186/S13059-023-03023-7
Abstract: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 in iduals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. We report the analysis of 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 s led breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.
Publisher: Wiley
Date: 23-12-2021
DOI: 10.1002/ART.41929
Abstract: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune‐related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene‐based aggregate testing, together with rare variant– and gene‐level enrichment analyses, was implemented to explore genotype–phenotype relations. Gene‐based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L , as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
Publisher: Oxford University Press (OUP)
Date: 06-08-2015
DOI: 10.1093/BIOINFORMATICS/BTV426
Abstract: Summary: High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them. Results: We present cgmisc, an R package that enables enhanced data analysis and visualization of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualization of genomic data and utilizes the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data. Availability and implementation: The package is operating system-independent and is available from: gmisc-team/cgmisc Contact: marcin.kierczak@imbim.uu.se Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth’s vast and imperiled bio ersity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
DOI: 10.1038/S41598-018-26842-2
Abstract: Autoimmune Addison’s disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator ( AIRE ) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
No related grants have been discovered for Matteo Bianchi.