Genetic Analyses of Common Infections in the Avon Longitudinal Study of Parents and Children Cohort

Abstract

The burden of infections on an individual and public health is profound. Many observational studies have shown a link between infections and the pathogenesis of disease; however a greater understanding of the role of host genetics is essential. Children from the longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children, had 14 antibodies measured in plasma at age 7: Alpha-casein protein, beta-casein protein, cytomegalovirus, Epstein-Barr virus, feline herpes virus, Helicobacter pylori, herpes simplex virus 1, influenza virus subtype H1N1, influenza virus subtype H3N2, measles virus, Saccharomyces cerevisiae, Theiler's virus, Toxoplasma gondii, and SAG1 protein domain, a surface antigen of Toxoplasma gondii measured for greater precision. We performed genome-wide association analyses of antibody levels against these 14 infections (N = 357 - 5010) and identified three genome-wide signals (P < 5×10^-8), two associated with measles virus antibodies and one with Toxoplasma gondii antibodies. In an association analysis focused on the human leukocyte antigen (HLA) region of the genome, we further detected 15 HLA alleles at a two-digit resolution and 23 HLA alleles at a four-digit resolution associated with five antibodies, with eight HLA alleles associated with Epstein-Barr virus antibodies showing strong evidence of replication in UK Biobank. We discuss how our findings from antibody levels complement other studies using self-reported phenotypes in understanding the architecture of host genetics related to infections.

Keywords: ALSPAC; HLA; antibody; genetics; infection.

Figure 1

The challenge of thresholding continuous antibody measures. Blue represents the distribution of uninfected individuals; Red represents the distribution of infected individuals. The green, orange, and purple dashed lines represent cut-off points. This figure depicts the theoretical overlap in antibody distribution of uninfected individuals (represented in blue) and infected individuals (represented in red), and the coloured dashed lines denotes how cut-offs may be selected. For example, the green threshold would include all infected individuals as cases, but also include a proportion of uninfected individuals as cases. Alternatively, the purple threshold would result in no uninfected individuals included as cases, but miss some that are infected. The orange threshold may be ideal as it would minimise the proportion of individuals misclassified as either cases or controls. However, the true underlying two distributions are not separately observed and so can only ever be estimated from the overall distribution.

Figure 2

Ratio to standard distributions of the antibodies measured at the ALSPAC seven-year clinic. The red dashed line represents the ratio to standard threshold of >=1 and the black dashed line represents the subjective threshold based on visually identifying the trough in distributions for bimodal antibodies.