Informed dimension reduction of clinically-related genome-wide association summary data characterises cross-trait axes of genetic risk

Abstract

Genome-wide association studies (GWAS) have uncovered pervasive genetic overlap between common clinically related immune-mediated diseases (IMD). To distinguish axes of IMD risk, and extend genetic knowledge of rare IMDs and subtypes, we developed a Bayesian shrinkage approach to perform a disease-focused decomposition of IMD GWAS summary statistics. We derive 13 components which summarise the multidimensional patterns of IMD genetic risk including those related to raised eosinophil count and serum IP-10. Projection of UK Biobank data demonstrated the IMD-specificity and accuracy of our reduced dimension basis in independent datasets. By projecting 22 rare IMD or IMD subtypes onto the basis we were able to identify disease-discriminating components and suggest novel associations. Requiring only summary level data, our approach allows the genetic architectures across any range of clinically-related traits to be characterised in fewer dimensions, facilitating the analysis of studies with modest sample size, where classical GWAS approaches are challenging.

A global atlas of genetic associations of 220 deep phenotypes

“…To address this, gathering of the genetic association statistics of hundreds of different phenotypes can dissect genotype-phenotype association patterns without a prior hypothesis, and identify latent structures underlying a spectrum of complex human traits. In particular, matrix decomposition on the summary statistics is a promising approach 5,32,33 , which derives orthogonal components that explain association variance across multiple traits while accounting for linear genetic architectures in general. This decomposition can address two challenges in current genetic correlation studies.…”

“…First, it informs us of genetic variants that explain the shared structure across multiple diseases, thereby enabling functional interpretation of the component. Second, it can highlight sub-significant associations and less powered studies, which are important in understanding the contribution of common variants in rare disease genetics with a small number of case samples 32 or in genetic studies in underrepresented populations where smaller statistical power is inevitable.…”

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study

“…Classes 1-3 were available in supplementary tables of Burren et al, 33 while GWAS summary data from FinnGen was accessed from its website. We used classes 1-2 to generate the hierarchical clustering, whereas we used classes 3-4 for comparisons based on Mahalanobis distance.…”

“…We chose to compare Takayasu arteritis to other IMDs through projecting it into a previously constructed lower-dimensional representation of IMD genetics, an ''IMD basis.'' 33 This representation uses 13 components to summarize axes of risk shared between different combinations of diseases. We found Takayasu arteritis differed significantly (FDR < 1%) from controls on eight of the 13 components, five of which were also associated with Crohn disease and/or ulcerative colitis.…”

HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole

“…BU may be driven by additional inflammatory genes since its genetic profile displayed shared genetic contributions with other inflammatory conditions, including systemic lupus erythema and Neuromyelitis optica , that both involve the eye ( 132 ). Among these may also be additional factors of the antigen presentation pathway, including the autophagy gene TECPR2 previously reported ( 34 ) or Killer immunoglobulin-Like Recepto r (KIR) (KIRs) genes ( 133 ).…”