The “Sum of Single Effects” (SuSiE) method of identifying relevant genetic variants appears to be superior to h2-D2 and FINEMAP for detecting genetic variables associated with primary biliary cholangitis (PCB), according to a recently published study in Genetic Epidemiology.
Genome-wide association studies (GWAS) look at the whole genome, searching for specific gene regions (loci) associated with a disease. Fine-mapping, on the other hand, identifies the actual genetic variants that produce the disease within loci identified by GWAS.
What is PBC?
Primary biliary cholangitis (PBC) is a rare, chronic autoimmune disease that primarily affects the liver. In PBC, the body’s immune system mistakenly attacks the small bile ducts within the liver, causing inflammation and gradual destruction of these ducts. Bile, a substance essential for digesting fats and removing toxins, becomes trapped in the liver, leading to liver damage over time.
But identifying more than one possible variant correlated with the disease in a single locus raises doubts about which of the two variables is actually causally associated with the disease.
Read more about PBC testing and diagnosis
“While numerous variants are reported as being causally associated with complex traits, false assignments of causality at the variant level are an important issue,” study authors said.
Fine-mapping in PBC: SuSiE vs. h2-D2
The last fine-mapping study in PBC analyzed 57 relevant loci identified in a previous GWAS study. Fine-mapping with the FINEMAP software successfully identified the causal variant in 29 out of 57 loci, with 16 remaining with more than one possible causal variant.
To address the gaps in the FINEMAP program, the authors analyzed the 57 loci with the SuSiE method and the h2-D2 method.
In general, both methods had good concordance with the FINEMAP results; however, in some loci, h2-D2 produced significantly more possible causal variants (credible sets).
The authors deemed the SuSiE results more plausible in most loci, and subsequent computer simulations further confirmed the initial assessment. These findings correlated with the results of previous research by different authors.
“Computer simulations suggest that, overall, SuSiE-RSS generally has slightly higher power, better precision, and better ability to identify the true number of causal variants in a region than h2-D2, although there are some scenarios where the power of h2-D2 is higher,” the authors wrote.
Fine-mapping studies have the potential to enable researchers to fully understand the pathophysiology of PBC in the most fundamental therapies. This knowledge can translate into developing novel, more effective therapeutic alternatives in the future.
