rs12198399 (TSBP1): Complement Proteins and Immunity

Key takeaways

• rs12198399 sits in the TSBP1 and TSBP1-AS1 locus within the major histocompatibility complex (MHC) region on chromosome 6, close to genes involved in the innate immune complement system.
• A genome-wide association study (GWAS) of 68,768 neonates identified loci in this region associated with circulating complement C3 and C4 protein concentrations.
• Genetically elevated C4 concentration was linked to altered risk across five types of autoimmune disorder through Mendelian randomization.
• Higher neonatal C3 was associated with reduced schizophrenia risk in females, but this was a post-hoc (secondary) finding that requires further study before firm conclusions can be drawn.
• GTEx data shows rs12198399 reduces STK19 gene expression in thyroid and tibial nerve tissue while increasing expression of nearby genes in skin and esophagus.

What the research says A genome-wide association study examining neonatal complement C3 and C4 protein concentrations in 68,768 individuals from the iPSYCH cohort identified 15 independent loci for C3 and 36 for C4, with the TSBP1 and TSBP1-AS1 locus (hereafter "the locus") among the regions implicated. Using C4 GWAS summary statistics in Mendelian randomization analyses, the study found evidence of altered risk across five categories of autoimmune disorder. In the full combined-sex sample, neither C3 nor C4 neonatal concentration was associated with six categories of mental disorder; a post-hoc sex-stratified analysis found that higher C3 was associated with reduced schizophrenia risk specifically in females.

Reported associations

• Complement C3 concentration (neonatal): The locus was among 15 independent genetic loci for circulating C3 protein concentration in a GWAS of 68,768 neonates; the available text does not report the effect size for this specific variant.
• Complement C4 concentration (neonatal): The locus was among 36 independent genetic loci for circulating C4 protein concentration in the same GWAS (n=68,768 neonates).
• Autoimmune disorders (Mendelian randomization): Genetically elevated C4 concentration was linked to altered risk across five types of autoimmune disorder; the specific conditions and effect sizes are not detailed in the available text.
• Schizophrenia risk (females only): Higher neonatal C3 concentration was associated with reduced schizophrenia risk in females in a post-hoc sex-stratified analysis; no effect was found in the combined-sex sample.

Evidence quality The primary GWAS was large (n=68,768 neonates from the iPSYCH cohort), providing strong statistical power to detect complement-associated loci. Specific p-values and effect sizes for rs12198399 alone are not reported in the provided text. The Mendelian randomization framework offers a causal inference approach stronger than standard association testing, but relies on assumptions including the absence of horizontal pleiotropy (when a variant affects the outcome through pathways other than the one being studied). The finding linking C3 concentration to reduced schizophrenia risk in females was a secondary, post-hoc analysis rather than a pre-specified primary hypothesis, which elevates the risk of a false-positive result; it should be interpreted cautiously until independently replicated. No specific replication data for this locus is described in the provided text.

Tissue-specific expression effects

• TSBP1 (ENSG00000308228): Increased expression in sun-unexposed suprapubic skin, sun-exposed lower-leg skin, and esophageal mucosa GTEx Portal
• STK19: Reduced expression in thyroid and tibial nerve tissue GTEx Portal
• TSBP1-AS1 (ENSG00000271581): Increased expression in tibial nerve, esophageal mucosa, and thyroid GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.