Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Abstract

Inflammation plays a key role in the development of complex diseases, such as cardiovascular disease,1 type 2 diabetes,2 Alzheimer disease,3 and schizophrenia.4 C-reactive protein (CRP) is a sensitive marker of chronic low-grade inflammation,5 and elevated serum amounts of CRP have been associated with a wide range of diseases.6–8 Unraveling the genetics of inflammation could provide further insights into the underlying biology of inflammation and could identify therapeutic targets for attenuating inflammation. The genetic determinants of CRP have only been partly characterized. In 2011, our group published a HapMap-based genome-wide association study (GWAS) meta-analysis including a discovery panel of up to 65,000 individuals and found 18 loci that were associated with amounts of CRP.9 Increasing GWAS sample size and denser mapping of the genome with further advanced imputation panels could help to identify further genes associated with the phenotypes of interest.10,11 Furthermore, by using genetic instrumental variables (i.e., a genetic score), Mendelian randomization (MR) allows investigation of the potential causal effect of an exposure on clinical outcomes and could help to elucidate the causal pathways that link the exposure with the outcome.12 The causal role of CRP in the development of diseases is still controversial,13 and the causal pathways that link inflammation to complex disorders are only partly understood. We applied two large-scale GWASs on circulatory amounts of CRP by using HapMap and 1000 Genomes (1KG) imputed data to identify genetic determinants of chronic inflammation. Because body mass index (BMI) is a major determinant of CRP amounts, we additionally conducted a GWAS adjusted for BMI to identify associated loci independent of BMI. To identify any sex differences in genetic determinants of chronic inflammation, we further conducted GWASs in men and women separately. We applied in silico functional analyses on the identified loci to obtain better insights into the biological processes potentially regulating chronic inflammation. Finally, we conducted MR analyses to provide an improved understanding of the causal relation between CRP and several related clinical outcomes.