Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The sex-stratified genetic architecture of ankylosing spondylitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting up

to three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed that

sex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven by

both rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-coding

loci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The male

specific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27

variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants from

each locus were shown to be functionally active in immune (Jurkat), skin (HaCat) and bone (SaOS-2) cell lines.

Differential patterns of genetic predisposition may point to alternative disease mechanisms in male and female

patients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and that

associated variants would likely affect gene regulation across multiple tissues. This work illustrates the need to

consider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.

Keywords [en]
ankylosing spondylitis, SKAT, RUNX3, MICB
National Category
Genetics
Research subject
Molecular Genetics; Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-390455OAI: oai:DiVA.org:uu-390455DiVA, id: diva2:1341719
Available from: 2019-08-10 Created: 2019-08-10 Last updated: 2019-09-24
In thesis
1. Complex disease genetics: Utilising targeted sequencing and homogeneous ancestry
Open this publication in new window or tab >>Complex disease genetics: Utilising targeted sequencing and homogeneous ancestry
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The complex disease investigations presented in this thesis aimed to provide new information regarding underlying genetics by using targeted sequencing and ethnically homogeneous cohorts. This work moved past current methodologies and addressed data stratification issues, that might have been hindering new findings. The results contribute to a more comprehensive view of the genetics of ankylosing spondylitis (AS) and breast cancer (BC), in Sweden.

Paper-I presents a sex-stratified analysis of a Swedish AS cohort that incorporated both common and rare variants. Single variant and aggregate tests both showed different signals in AS male and female patients, previously masked. Specifically, the RUNX3 locus in males (univariate test: rs7414934, OR=2.58, p=1.7x10-5) and MICB in females (SKAT: 27 variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. In the functional follow up of these loci, risk alleles appear to regulate the expression of genes in multiple tissues. Also, the results highlight the importance of disease regulation from different haplotypes and loci breakdown proved that Sweden’s genetic architecture might be critical for AS studies.

Paper-II is a replication study, in our modest-sized Swedish cohort, of AS associations, previously discovered in populations of British origin, Initially, power calculations assessed that the Swedish cohort had the power to replicate only published associated markers with high effect (OR > 7), e.g., HLA-B but the replication analysis revealed three associated loci (ORrange:1.9-2.7). Notably, the multiplicated HLA-B marker (rs4349859) was not in HWE equilibrium. Population structure differences could not explain this replication pattern. However, sequencing resolution revealed fine-scale differences with repositioned association signals in the known loci. Specifically, the identification of two CCHCR1 protective haplotypes (OR: 0.14/0.3) that affect other MHC gene expression through eQTLs, provided the first suggestion of the differential function of known associated loci with cis gene regulation.

Paper-III provides the first fingerprint of the somatic mutation profile of Swedish BC. The significantly mutated genes were PIK3CA (28%), TP53 (21%) and CDH1 (16%) while histone-modifying genes (e.g., KMT2C and ARID1A: together 28%) exhibited an increased somatic mutation prevalence, not observed previously. Additionally, within the patients that did not receive neoadjuvant treatment, there were distinct age groups with different mutational profiles and differential APOBEC signature driving genes.

Taken together, these studies emphasize the contribution to the underlying genetics deriving from smaller ethnic populations, when assessed with a shift in methodology to account for biological bias, like sex and age. The results will hopefully assist and guide other genetic studies of human complex disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1588
Keywords
ankylosing spondylitis, breast cancer, targeted sequencing, Sweden, genetics, population stratification.
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-390457 (URN)978-91-513-0710-7 (ISBN)
Public defence
2019-09-27, Room B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note

Exact room will be known the 12th August. Booking system was down due to summer vacation

Available from: 2019-09-04 Created: 2019-08-10 Last updated: 2019-09-17
2. Human leukocyte antigen in sickness and in health: Ankylosing spondylitis and HLA in Sweden
Open this publication in new window or tab >>Human leukocyte antigen in sickness and in health: Ankylosing spondylitis and HLA in Sweden
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human leukocyte antigen (HLAplays a major role in keeping us healthy, but some of the HLA alleles can contribute to disease susceptibility. One example is HLA-B*27which confers increased susceptibility of ankylosing spondylitis and represents one of the strongest genetic associations found in any common human disease. Ankylosing spondylitis shows a strong sex ratio skew (2-3:1 male to female) and studies confirm the existence of sexual-dimorphism in the presentation of this disease. The genetic predisposition for this, however, has not previously been studied. 

A Swedish ankylosing spondylitis population was sequenced with a targeted array to investigate the existence of sex-specific associations. RUNX3 was revealed to be associated in males by a univariate test, while aggregate tests revealed the HLA gene MICB to be associated in females. Functional validation demonstrated that the risk variants in RUNX3 increase expression, and MICB changed the transcription factor binding sites. Interestingly, since the disease involves bone changes, both RUNX3 and one of the MICB variants had effect in the bone cell line, SaOS-2.

In order to help researchers obtain more controls for HLA analysis, an HLA allele bioresource (SweHLA) was generated from 1,000 Swedish genomes. The alleles were typed with three to four HLA typing software programs and results were combined by an n-1methodology. This produced high quality alleles where the bias from each software program was diminished.

The methodology from SweHLA was utilised to study HLA in ankylosing spondylitis. To investigate both sex-specific predisposition and HLA-B*27 independence, samples were subdivided into two populations (one population with mixed HLA-B*27 positive and negative samples and one with only HLA-B*27 positive samples) that in turn were grouped by sex. In the mixed population, several alleles were replicated from previous studies. This study also revealed three female-specific alleles, two of which were new and one that had previously been associated to the severity of radiological changes. The HLA-B*27 population revealed a previously unknown protective allele, HLA-A*24:02. Through deeper examination of the HLA-B*27 population, two amino acids in HLA-A, position 119 in the whole set and position 180 in the male set, were revealed to be protective.

This thesis brings new insight into the genetic predisposition for a sex-skewed disease, demonstrating how sexual-dimorphism can be reflected in the genetic predisposition, hopefully leading to more similar studies. It also highlights the importance of methodology and demonstrate the drastic biases that can be imparted by software programs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1599
Keywords
Disease genetics, Ankylosing spondylitis, HLA typing, Imputation, Inference, Sex-stratified, HLA-B*27 independent, Association tests, Functional validation
National Category
Bioinformatics (Computational Biology) Medical Genetics Genetics
Research subject
Bioinformatics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-393317 (URN)978-91-513-0760-2 (ISBN)
Public defence
2019-11-14, Room B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-10-23 Created: 2019-09-24 Last updated: 2019-11-12

Open Access in DiVA

Supplementary data Table S8_3(100 kB)3 downloads
File information
File name DATASET01.zipFile size 100 kBChecksum SHA-512
2ace26352005b90e4131214c8e9b5a7bc40bb9d36dde5e9d9ad79f82ec8908ca3edb3ce3c87bbf988b2d584d1a6bc528014e99ebf64d66c728b64c524519c091
Type datasetMimetype application/zip
Supplementary data Table S16_4(19 kB)3 downloads
File information
File name DATASET02.zipFile size 19 kBChecksum SHA-512
391b1eb5af737a3049bd6ac98924d5a648216141adcdf11dfe7e6382b46f80495093836d7134c43a8452123c890cc689b83f2c0756b60f4f4081384f527844f2
Type datasetMimetype application/zip

Search in DiVA

By author/editor
Mathioudaki, ArgyriNordin, JessikaKarlsson, ÅsaMurén, EvaBianchi, MatteoPettersson, MatsFarias, Fabiana H. G.Dahlqvist, JohannaPielberg, GerliLindblad-Toh, KerstinMeadows, Jennifer
By organisation
Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and Pathology
Genetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 0 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

urn-nbn

Altmetric score

urn-nbn
Total: 73 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf