Abstract
Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer's disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β 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 S100β 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 S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer's disease. Colocalisation between S100β and Alzheimer's disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10 -8) with S100β protein levels. The lead variant was located in the S100β gene (rs8128872, P=5.0x10 -17). We found evidence that two independent causal variants existed for both transcription of S100β and S100β protein levels in our eQTL analyses . No CpG sites were associated with S100β 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 S100β levels and Alzheimer's disease or vice versa and no evidence for colocalisation between S100β and Alzheimer's disease loci. Conclusions: These data provide insight into the molecular regulators of S100β levels. This context may aid in understanding the role of S100β in brain inflammation and neurological disease.
Highlights
The calcium-binding protein S100 beta (S100β) has been suggested as a biomarker for central nervous system disease1
The S100β gene was identified as a site of differential DNA methylation (DNAm) relating to Braak staging in a previous epigenome-wide association study (EWAS) of cortical post-mortem tissues (n=159)13
Genetic profiling of S100β The linear regression genome-wide association study identified 154 SNPs (Figure 2, full summary statistics are available in the Extended Data) on chromosome 21 that were associated with S100β levels at P < 5 × 10-8 (N=769)
Summary
The calcium-binding protein S100 beta (S100β) has been suggested as a biomarker for central nervous system disease. The exact pathophysiology is still unknown, a number of small-scale studies have reported elevated circulating or cerebrospinal fluid (CSF) S100β levels in individuals with nervous system injury, neuroinflammatory conditions, white matter ageing and Alzheimer’s dementia and delirium. Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer’s disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer’s disease. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. We found evidence that two independent causal variants existed for both transcription of S100β and S100β protein levels in our eQTL analyses.
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