ABSTRACT
Background: Circulating S100 calcium-binding protein (S100ß) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100ß and its potential causal associations with Alzheimer's disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100ß levels in older adults and performed Mendelian randomisation with Alzheimer's disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100ß levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100ß. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100ß and Alzheimer's disease. Colocalisation between S100ß and Alzheimer's disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10 -8) with S100ß protein levels. The lead variant was located in the S100ß gene (rs8128872, P=5.0x10 -17). We found evidence that two independent causal variants existed for both transcription of S100ß and S100ß protein levels in our eQTL analyses . No CpG sites were associated with S100ß levels at the epigenome-wide significant level (P<3.6x10 -8); the lead probe was cg06833709 (P=5.8x10 -6), which mapped to the LGI1 gene. There was no evidence of a causal association between S100ß levels and Alzheimer's disease or vice versa and no evidence for colocalisation between S100ß and Alzheimer's disease loci. Conclusions: These data provide insight into the molecular regulators of S100ß levels. This context may aid in understanding the role of S100ß in brain inflammation and neurological disease.