The sex-stratified genetic architecture of ankylosing spondylitis

• Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting upto three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed thatsex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven byboth rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-codingloci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The malespecific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants fromeach 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 femalepatients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and thatassociated variants would likely affect gene regulation across multiple tissues. This work illustrates the need toconsider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.

Subject headings

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

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

Keyword

ankylosing spondylitis

SKAT

RUNX3

MICB

Molekylär genetik

Molecular Genetics

Molekylär genetik

Molecular Genetics

Publication and Content Type

vet (subject category)

ovr (subject category)