Large registry-based analysis of genetic predisposition to tuberculosis identifies genetic risk factors at HLA

Abstract

Tuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1895 individuals in the FinnGen study had International Classification of Diseases-based tuberculosis diagnosis. Genome-wide association study analysis identified genetic variants with statistically significant association with tuberculosis at the human leukocyte antigen (HLA) region (P < 5e-8). Fine mapping of the HLA association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (P = 1.82E-06, OR = 0.81 [CI 95% 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (P = 0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (P < 0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted P < 0.05, OR = 1.83 [CI 95% 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.

Figure 1

FinnGen R7 distribution of tuberculosis diagnosis and age at first diagnosis. (A) A bar chart illustrating diagnosed tuberculosis cases by year of diagnosis in FinnGen R7 starting from 1970 (start of the Care Register for Health Care Inpatient Visits in Finland) until the end of 2019 (end of follow-up time December 31, 2019). (B) A bar chart illustrating diagnosis age in individuals with tuberculosis (age range is from birth to 100 years of age).

Figure 2

A Manhattan plot from a tuberculosis GWAS in FinnGen R7. (A) Manhattan plot from GWAS in 1895 individuals with ICD-based tuberculosis and 307 259 controls from FinnGen R7 where each dot represents an SNP from chromosome 1–23. The lead variants, rs9391858 and rs560595454, and their respective P-values are marked to their corresponding positions. r² values represent the linkage disequilibrium (LD) between the lead variant (rs9391858) and the respective HLA alleles.

Figure 3

HLA fine mapping. Association of HLA alleles with tuberculosis in FinnGen R7 (cut off P-value 0.05).

Figure 4

Error bar plot on association of known risk factors with tuberculosis and Mendelian randomization analysis (MR) with smoking trait. (A) Bar plot demonstrates odds ratios (OR) and their respective 95% confidence intervals between tuberculosis and risk factors. From the studied risk factors (Supplementary Material, Table S5), RA (rheumatoid arthritis), IBD (inflammatory bowel disease), ever smoker, current smoker, Crohn’s disease, COPD (chronic obstructive pulmonary disease), CHD (major coronary heart disease event), biological medication for rheumatoid arthritis (Bio.med. RA), AUD (alcohol use disorder), asthma and alcohol dependence had statistically significant and positive association with tuberculosis. (B) MR suggests habitual smoking (instrumented by cigarettes per day) as a risk factor for tuberculosis (inverse-variance weighted P = 0.01). The increase of habitual smoking increases the risk for tuberculosis.