The genetic and epigenetic profile of serum S100β in the Lothian Birth Cohort 1936 and its relationship to Alzheimer’s disease

Wellcome Open Research

article

Danni A Gadd¹  Robert I McGeachan²  Robert F Hillary¹  Daniel L McCartney¹  Sarah E Harris³  Roy A Sherwood⁵  N Joan Abbott⁶  Simon R Cox³  Riccardo E Marioni¹ 

[1] Institute of Genetics and Cancer, University of Edinburgh;Centre for Discovery Brain Sciences, University of Edinburgh;Lothian Birth Cohorts, University of Edinburgh;Department of Psychology, University of Edinburgh;Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust;Institute of Pharmaceutical Science, King's College London

关键词: Epigenetic;    Genetic;    S100β;    Inflammation;    EWAS;    GWAS;    Alzheimer's disease;   

DOI  :  10.12688/wellcomeopenres.17322.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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 theS100β gene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription ofS100β 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 theLGI1 gene. There was no evidence of a causal association between S100β levels and Alzheimer’s disease or vice versa and no evidence for colocalisation betweenS100β 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.

【 授权许可】

CC BY