Genome-wide associations identify novel candidate loci associated with genetic susceptibility to tuberculosis in wild boar

Abstract

Tuberculosis (TB) affects a wide range of host species worldwide. Understanding host-pathogen co-evolution remains a global challenge owing to complex interactions among host genetic factors, pathogen traits and environmental conditions. We used an endemic wild boar population that had undergone a huge increase in Mycobacterium bovis infection prevalence, from 45% in 2002/06 to 83% in 2009/12, to understand the effects of host genetics on host TB outcomes and disease dynamics. Host genomic variation was characterized using a high-density single nucleotide polymorphism (SNP) array, while host TB phenotype was assessed using both gross pathology and mycobacterial culture. Two complementary genome-wide association (GWAS) analyses were conducted: (i) infected-uninfected; and (ii) 2002/06-2009/12. The SNPs with the highest allelic frequency differences between time-periods and TB outcomes were identified and validated in a large dataset. In addition, we quantified the expression levels of some of their closest genes. These analyses highlighted various SNPs (i.e. rs81465339, rs81394585, rs81423166) and some of the closest genes (i.e. LOC102164072, BDNF/NT-3, NTRK2, CDH8, IGSF21) as candidates for host genetic susceptibility. In addition to TB-driven selection, our findings outline the putative role of demographic events in shaping genomic variation in natural populations and how population crashes and drift may impact host genetic susceptibility to TB over time.

Figure 1

Plot showing the wild boar population abundance (dashed line) and tuberculosis prevalence (solid line) estimated for each season (number of individuals = #) throughout the monitored program implemented in the reserve and the sampling period, respectively. The three population crashes are also indicated.

Figure 2

Historical trajectories of effective population size (N_e) of the wild boar population inferred from genomic data for the past generations.

Figure 3

Minor allele frequencies (MAF) differentiation for the singular nucleotide polymorphism (SNP) identified in genome-wide association (GWAS) analyses. MAF differences are shown between (a) time-periods (2002/06 vs. 2009/12) and (b) tuberculosis (TB) outcome (uninfected vs. infected). The location of each SNP on porcine genome assembly Sus scrofa 10.2, and the closest genes are also represented. The candidate genes selected for mRNA gene expression analyses are indicated in bold type.

Figure 4

Manhattan plot displaying the genome-wide results [−log10(P)] of the standard (a) and stratified (b) association analyses between uninfected and infected individuals with Mycobacterium tuberculosis complex (MTC).

Figure 5

Biological function of genes associated to SNPs with the highest allele frequency differences in the standard and/or stratified genome-wide analyses (GWAS).

Figure 6

Manhattan plot displaying the genome-wide results [−log10(P)] of the standard (a) and stratified (b) association analyses between the 2002/06 and 2009/12 time-periods.