Replication and fine mapping of ankylosing spondylitis replicated loci in the Swedish population reveal different CCHCR1 protective haplotypes

• 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 (0.2-3), 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, r2 < 0.3). The CCHCR1 locus showed two protective haplotype blocks (B1-1 and B2-1), independent from HLA-B signals (B1-1: r2 = 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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Genetik (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Genetics (hsv//eng)

Nyckelord

Ankylosing spondylitis

Swedish population

HLA-B27

CCHCR1

TCF19

POU5F1.

Molekylär genetik

Molecular Genetics

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)