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

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.This research was supported by: Portuguese national funds through the FCT (Fundação para a Ciência e a Tecnologia) and FEDER funds (Fundo Europeu de desenvolvimento Regional) through the Programa Operacional Potencial Humano-Quadro de Referência Estratégico Nacional (POPH-QREN) from the European Social Fund and Portuguese Ministério da Educação e Ciência (SFRH/BD/73732/2010 PhD grant to JQ); AGL2014-56305 and IPT-2011-0735-010000 grants from the Ministerio de Economía y Competitividad, Spain and EU-FEDER; and the European Union Horizon 2020 COMPARE Grant 377/14.Peer reviewedPeer Reviewe