A genome-wide association study of pulmonary tuberculosis in Morocco

Abstract

Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10−4. The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10−6 < p < 4 × 10−5): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10−6) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.

A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility

“…However, the power to detect a common variant with an odds ratio of 2 was 98%. Validation of these results in other case-control cohorts as well as the inclusion of recent GWAS results [5,12,14] is desirable, but complicated by the lack of available TB case-control cohorts with a similar genetic structure to that of the SAC population. In addition, since there was a priori evidence for an association, replication is arguably not necessary as this study attempted to fine-map the potential causal variants in loci identified by previous TB GWAS.…”

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…The authors concluded that ADA2 might be important for the regulation of the innate immune responses against MTB infection. Interestingly a recent genome wide association studies (GWAS) failed to identify ADA2 as a common susceptibility locus for MTB infection . However, it is prudent to say that GWAS typically interrogate polymorphisms and that rare variants may be overlooked.…”

“…Interestingly a recent genome wide association studies (GWAS) failed to identify ADA2 as a common susceptibility locus for MTB infection. 33 However, it is prudent to say that GWAS typically interrogate polymorphisms and that rare variants may be overlooked. On the viral side, plasma ADA2 has been used as a marker for HIV-1 seroconversion and HTLV infection.…”

Genomics of Human Pulmonary Tuberculosis: from Genes to Pathways

“…A case-control GWAS in a Russian population replicated the chromosome 11 locus, but not the chromosome 18 locus; it also detected significant association with the ASAP1 gene [44]. While a GWAS conducted in a Moroccan population did not detect any genome-wide significant associations, it replicated results from chromosomes 11 and 18 at a nominal significance (p<0.05) [45]. A GWAS in an Indonesian population did not detect any loci that were significant after multiple testing correction, although it did identify suggestively associated loci involved in immune signaling; the previous GWAS associations were not explicitly tested in this study [46].…”