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Halvardson, Jonatan
Publications (10 of 20) Show all publications
Thompson, D. J., Genovese, G., Halvardson, J., Ulirsch, J. C., Wright, D. J., Terao, C., . . . Perry, J. R. (2019). Genetic predisposition to mosaic Y chromosome loss in blood. Nature, 575, 652-657
Open this publication in new window or tab >>Genetic predisposition to mosaic Y chromosome loss in blood
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2019 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 575, p. 652-657Article in journal (Refereed) Published
Abstract [en]

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397756 (URN)10.1038/s41586-019-1765-3 (DOI)000500036800057 ()31748747 (PubMedID)
Funder
EU, European Research Council, 679744
Note

Lars Forsberg and John Perry contributed equally to this work

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-01-13Bibliographically approved
Lindholm Carlström, E., Halvardson, J., Etemadikhah, M., Wetterberg, L., Gustavson, K.-H. & Feuk, L. (2019). Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family. BMC Medical Genomics, 12(1), Article ID 156.
Open this publication in new window or tab >>Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family
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2019 (English)In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 12, no 1, article id 156Article in journal (Refereed) Published
Abstract [en]

Background

Non-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.

Methods

Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton (TM) System. Validation of identified variants was performed with Sanger sequencing.

Results

The linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.

Conclusions

DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.

Keywords
Affymetrix genome-wide human SNP Array 6, 0, Complex disorder, Genome wide analysis, Large pedigree, Sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397672 (URN)10.1186/s12920-019-0606-4 (DOI)000495622100001 ()31694657 (PubMedID)
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Danielsson, M., Halvardson, J., Davies, H., Moghadam, B. T., Mattisson, J., Rychlicka-Buniowska, E., . . . Forsberg, L. A. (2019). Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals. European Journal of Human Genetics
Open this publication in new window or tab >>Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed) Epub ahead of print
Abstract [en]

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397754 (URN)10.1038/s41431-019-0533-z (DOI)31654039 (PubMedID)
Note

These authors contributed equally: Jan P. Dumanski, Lars A. Forsberg

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Forsberg, L. A., Halvardson, J., Rychlicka-Buniowska, E., Danielsson, M., Moghadam, B. T., Mattisson, J., . . . Dumanski, J. P. (2019). Mosaic loss of chromosome Y in leukocytes matters [Letter to the editor]. Nature Genetics, 51(1), 4-7
Open this publication in new window or tab >>Mosaic loss of chromosome Y in leukocytes matters
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal, Letter (Other academic) Published
National Category
Medical Genetics Genetics
Identifiers
urn:nbn:se:uu:diva-373366 (URN)10.1038/s41588-018-0267-9 (DOI)000454108800004 ()30374072 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Johansson, M., Pottmeier, P., Suciu, P., Ahmed, T., Zaghlool, A., Halvardson, J., . . . Jazin, E. (2019). Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development. Frontiers in Genetics, 10, Article ID 891.
Open this publication in new window or tab >>Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development
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2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 891Article in journal (Refereed) Published
Abstract [en]

Global microarray gene expression analyses previously demonstrated differences in female and male embryos during neurodevelopment. In particular, before sexual maturation of the gonads, the differences seem to concentrate on the expression of genes encoded on the X- and Y-chromosomes. To investigate genome-wide differences in expression during this early developmental window, we combined high-resolution RNA sequencing with qPCR to analyze brain samples from human embryos during the first trimester of development. Our analysis was tailored for maximum sensitivity to discover Y-chromosome gene expression, but at the same time, it was underpowered to detect X-inactivation escapees. Using this approach, we found that 5 out of 13 expressed game to log pairs showed unbalanced gene dosage, and as a consequence, a male-biased expression. In addition, we found six novel non-annotated long non-coding RNAs on the Y-chromosome with conserved expression patterns in newborn chimpanzee. The tissue specific and time-restricted expression of these long non-coding RNAs strongly suggests important functions during central nervous system development in human males.

Keywords
sex differences, gene expression, X-chromosome, Y-chromosome, long non-coding RNA, RNA sequencing, human brain development, Pan troglodytes
National Category
Genetics Medical Genetics
Identifiers
urn:nbn:se:uu:diva-395797 (URN)10.3389/fgene.2019.00891 (DOI)000487628500001 ()
Funder
Swedish Research Council, K2012-61X-22089-01-3EU, European Research Council, 282330
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved
Thuresson, A.-C., Zander, C., Zhao, J. J., Halvardson, J., Maqbool, K., Månsson, E., . . . Feuk, L. (2019). Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability [Letter to the editor]. Clinical Genetics, 95(3), 436-439
Open this publication in new window or tab >>Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
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2019 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, no 3, p. 436-439Article in journal, Letter (Refereed) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-326281 (URN)10.1111/cge.13470 (DOI)000458956100013 ()30525197 (PubMedID)
Funder
EU, European Research Council, 282330
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2019-03-14Bibliographically approved
Zhao, J. J., Halvardson, J., Zander, C., Zaghlool, A., Georgii-Hemming, P., Månsson, E., . . . Feuk, L. (2018). Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177(1), 10-20
Open this publication in new window or tab >>Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
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2018 (English)In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, no 1, p. 10-20Article in journal (Refereed) Published
Abstract [en]

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326280 (URN)10.1002/ajmg.b.32574 (DOI)000417876700002 ()28990276 (PubMedID)
Funder
EU, European Research Council
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-17Bibliographically approved
Zhao, J. J., Halvardson, J., Knaus, A., Georgii-Hemming, P., Baeck, P., Krawitz, P., . . . Feuk, L. (2017). Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function. Human Mutation, 38(10), 1394-1401
Open this publication in new window or tab >>Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function
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2017 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 10, p. 1394-1401Article in journal (Refereed) Published
Abstract [en]

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.

Keywords
PIGG, GPI deficiency, Intellectual disability, Exome sequencing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326282 (URN)10.1002/humu.23268 (DOI)000411740400013 ()
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-02-02Bibliographically approved
Halvardson, J., Zhao, J. J., Zaghlool, A., Wentzel, C., Georgii-Hemming, P., Månsson, E., . . . Feuk, L. (2016). Mutations in HECW2 are associated with intellectual disability and epilepsy. Journal of Medical Genetics, 53(10), 697-704
Open this publication in new window or tab >>Mutations in HECW2 are associated with intellectual disability and epilepsy
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2016 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, no 10, p. 697-704Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Intellectual disability; Epilepsy; Exome sequencing; HECW2; ERC2
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-301393 (URN)10.1136/jmedgenet-2016-103814 (DOI)000385958500008 ()27334371 (PubMedID)
Funder
EU, European Research Council, 282330Swedish Society for Medical Research (SSMF)
Available from: 2016-08-31 Created: 2016-08-22 Last updated: 2018-01-10Bibliographically approved
Halvardson, J. (2016). Sequence based analysis of neurodevelopmental disorders. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Sequence based analysis of neurodevelopmental disorders
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the main focus is the use of methods and applications of next generation sequencing in order to study three of the most common neurodevelopmental disorders: intellectual disability, epilepsy and schizophrenia. A large fraction of the genes in our genome produce several distinct transcript isoforms through the process of splicing and there is an increasing amount of evidence pinpointing mutations affecting splicing as a mechanism of disease.  In Paper I we used exome capture of RNA in combination with sequencing in order to enrich for coding sequences. We show that this approach enables us to detect lowly expressed transcript and splice events that would have been missed in regular RNA sequencing using the same coverage.  In Paper II we selectively depleted the different transcripts of Quaking (QKI), a gene previously associated to schizophrenia. Using RNA sequencing we show that the effects of depletion differ between transcripts and that the QKI gene is a potential regulator of the Glial Fibrillary Acidic Protein (GFAP), a gene implicated in several diseases in the central nervous system.

De-novo mutations are frequently reported to be causative in neurodevelopmental disorders with a strong genetic component, such as epilepsy and intellectual disability. In Paper III we used exome sequencing in family trios where the child was diagnosed with both intellectual disability and epilepsy, focusing on finding de-novo mutations. We identified several previously unknown disease causing mutations in genes previously known to cause disease and used previously published interaction and mutation data to prioritize novel candidate genes. The most interesting result from this study are the implication of the HECW2 gene as a candidate gene in intellectual disability and epilepsy. In Paper IV we used RNA sequencing of post mortem brain tissue in a large cohort of schizophrenics and controls.  In this study we could show that the immune system and more specifically the complement system was dysregulated in a large fraction of patients. Further, using co-expression network we also found some evidence suggesting genes involved in axon development and maintenance.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1231
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-287407 (URN)978-91-554-9597-8 (ISBN)
Public defence
2016-06-14, C2:305, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2016-05-20 Created: 2016-04-24 Last updated: 2018-01-10
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