Integrative omics approach to identify the molecular architecture of inflammatory protein levels in healthy older adults

Abstract

The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. Therefore, in this study, we perform genome-and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares-(OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified three CpG sites spread across three proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to one polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease, and between IL12B and Crohn's disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

“…For BayesR+ GWAS data, see https://datashare.is. ed.ac.uk/handle/10283/3673; https://doi.org/10.7488/ds/2854 [102]. For OLS regression EWAS data, see https://datashare.is.ed.ac.uk/handle/10283/3628, https://doi.org/10.7488/ds/2818 [103].…”

“…For OLS regression EWAS data, see https://datashare.is.ed.ac.uk/handle/10283/3628, https://doi.org/10.7488/ds/2818 [103]. For OSCA EWAS data, see https:// datashare.is.ed.ac.uk/handle/10283/3627, https://doi.org/10.7488/ds/2817 [104]. For BayesR+ EWAS data, see https://datashare.is.ed.ac.uk/handle/102 83/3626; https://doi.org/10.7488/ds/2816 [105].…”

“…For OSCA EWAS data, see https:// datashare.is.ed.ac.uk/handle/10283/3627, https://doi.org/10.7488/ds/2817 [104]. For BayesR+ EWAS data, see https://datashare.is.ed.ac.uk/handle/102 83/3626; https://doi.org/10.7488/ds/2816 [105]. Summary statistics for the OLS GWAS data are also available at GWAS Catalog (https://www.ebi.ac.uk/ gwas/; Study Accessions: GCST90000437-GCST90000506) [106].…”

Blood-based epigenome-wide analyses of cognitive abilities

“…BMI, six metre walk time, and units of alcohol were log transformed to reduce skew -a constant of one was added to the alcohol units prior to transforming. An Olink panel of inflammation-related proteins[37], measured on blood samples at age 70 years in LBC1936, were related to both EpiScore g and measured g in age-and sex-adjusted linear regression models. An additional panel of Olink neurology-related proteins[16,37], measured on blood samples at age 73 years in LBC1936, were related to EpiScore g, access protocol[39].…”

“…An Olink panel of inflammation-related proteins[37], measured on blood samples at age 70 years in LBC1936, were related to both EpiScore g and measured g in age-and sex-adjusted linear regression models. An additional panel of Olink neurology-related proteins[16,37], measured on blood samples at age 73 years in LBC1936, were related to EpiScore g, access protocol[39]. A 1.5 T GE Signa HDx clinical scanner (General Electric, Milwaukee, WI, USA) was used to collect structural T1-(voxel size = 1 × 1 × 1.3 mm), T2-(voxel size =…”