Research Questions:
– Which genetic variants are significantly associated with serum CSTB levels in the general population?
– Can known CSTB pathogenic variants (e.g., the dodecamer repeat in the promoter) be linked to lower serum CSTB levels in individuals without known genetic disorders?
– Is there evidence for subclinical phenotypes-such as reduced cerebellar volume-in carriers of CSTB variants?
Research Objectives:
To systematically identify and classify CSTB gene variants associated with variations in serum CSTB protein levels.
To determine whether known pathogenic variants can be detected and quantified in a large-scale, healthy cohort.
To explore potential phenotypic effects of CSTB variants through correlation with imaging data, focusing on cerebellar volume.
To establish a normative reference range for serum CSTB expression in the general population and assess its utility for detecting carrier status.
Scientific Rationale:
CSTB encodes cystatin B, a protein implicated in Unverricht-Lundborg disease (ULD), with pathogenic mutations commonly affecting its promoter region. The UK Biobank provides a unique opportunity to investigate the genetic regulation of CSTB protein levels at a population scale, especially in asymptomatic individuals. Early analysis reveals associations between known CSTB mutations and reduced serum CSTB levels, as well as structural brain differences. Understanding these associations may not only improve carrier detection and establish reference laboratory values but also reveal potential subclinical phenotypes in heterozygous individuals. This study leverages state-of-the-art population genomics and imaging datasets to bridge molecular findings with potential clinical implications.
Methodological Overview:
Utilize the UK Biobank Research Analysis Platform (RAP) to access genetic, biochemical, and imaging data.
Perform genotype-phenotype association analyses between CSTB variants and serum CSTB concentrations using pQTL
