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Replication and fine mapping of ankylosing spondylitis replicated loci in the Swedish population reveal different CCHCR1 protective haplotypes
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.
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.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The genetics of ankylosing spondylitis (AS) derives mainly from studies performed in large cohorts of British origin. However, within Europe, disease prevalence is higher in Sweden, and so we investigated the reproducibility of known AS susceptibility patterns in a homogeneous Swedish cohort.

Methods: The replication power of the Swedish cohort was examined and a set of published SNP associations intersected with genotypes from an existing targeted sequencing study using these individuals (381 controls; 310 AS cases). To elucidate whether replication patterns derived from population subsampling or genetic similarity, allele frequency data from additional British and Swedish control populations were examined for genetic differentiation (FST). Replicated loci were fine mapped to investigate associations in more detail, and signals were dissected with haplotype analysis and functional annotation.

Results: The study had 80% power to find variants of strong effect (Odds ratio, OR>2) given a wide range of risk allele frequencies (0.2<RAF<0.8). From a set of 40 markers (33 gene loci), four variants were replicated (p-value < 1.25 x10-3), tagging HLA-B,CCHCR1and IL23R. The replication pattern was not due to European population genetic distance and fine mapping revealed genome-wide repositioned associations in HLA-Band CCHCR1, independent from the published associations (p-value < 2 x10-8, r< 0.3). The CCHCR1 locus showed two protective haplotype blocks (B1-1 and B2-1), independent from HLA-B signals (B1-1: r= 0.39, B2-2:r2=0.07), where 74% of controls were carrying 2 copies of the protective haplotypes (B1-1 and B2-1: OR=0.3, p-value = 1.2 x 10-45). Interestingly, while both haplotypes span CCHCR1, the effect of each haplotype is likely in cis, with eQTL evidence pointing to the regulation of TCF19(B1-1) and POU5F1(B1-2).

Conclusions: Both European populations share key disease loci, but the Swedish cohort revealed fine-scale genetic differences, that may point to gene regulation. This study utilized a different variant resolution, and by doing so demonstrated that smaller populations have the potential to reveal new AS pathogenesis mechanisms and that further study of the Swedish population is warranted.

Keywords [en]
Ankylosing spondylitis, Swedish population, HLA-B27, CCHCR1, TCF19, POU5F1.
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-390452OAI: oai:DiVA.org:uu-390452DiVA, id: diva2:1341718
Note

Please do not publish online in DiVa before publication: manuscript under review

Available from: 2019-08-10 Created: 2019-08-10 Last updated: 2019-08-10
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

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Mathioudaki, ArgyriNordin, JessikaMurén, EvaKarlsson, ÅsaPielberg, GerliLindblad-Toh, KerstinMeadows, Jennifer

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