A Genome-wide Association Study of Susceptibility to Upper Urinary Tract Infections

Abstract

Background: Our goal was to identify genetic and modifiable risk factors for upper urinary tract infections (UTIs).

Methods: We used data from UK Biobank, the Trøndelag Health Study, and the Michigan Genomics Initiative to conduct genome-wide association studies and sex-stratified analyses on upper UTI. Mendelian randomization (MR) analyses were conducted to examine potential causal relationships between cardiometabolic risk factors and upper UTIs.

Results: One genome-wide significant (P ≤ 5E-08) locus was associated with the susceptibility to upper UTI, located near TSN in the female-only analysis. Additionally, we identified suggestive (P ≤ 5E-06) loci near DNAI3 for females, SCAMP1-AS1 for males, and near TSN, LINC00603, and HLA-DQA2 for both sexes. In MR analyses, higher genetically predicted lifetime smoking scores were associated with an increased risk of developing upper UTI for females and both sexes (odds ratio [OR], 4.84, P = 4.50E-06 and OR, 2.79, P = 3.02E-05, respectively).

Conclusions: We found that genetic variants near TSN was associated with the risk of upper UTIs among females. In addition, we found several genetic loci with suggestive associations with the risk of upper UTIs. Finally, MR analyses found smoking to be a potential causal risk factor for upper UTIs.

Keywords: Mendelian randomization; genome-wide association study; pyelonephritis; smoking; upper urinary tract infection.

Figure 1.

Miami plot of the genome-wide association analysis for the risk of upper urinary tract infection for the sex-stratified meta-analyses. The x-axis shows the genomic position (chromosomes 1–23; where 23 is the X chromosome), and the y-axis represents the negative logarithm (base 10) of the variant P value. The blue lines indicates genome-wide suggestive associations (P ≤ 1E-06), and the red lines indicates genome-wide significant associations (P ≤ 5E-08). The red Manhattan plot indicates the female-only genome-wide association study (GWAS), and the blue Manhattan plot indicates male-only GWAS. Genome-wide significant or suggestive loci in the female- or male-only analysis (±500 kb of lead variant) are highlighted in green.

Figure 2.

Manhattan plot of the genome-wide association analysis for the risk of upper urinary tract infection for the meta-analysis of both sexes. The x-axis shows the genomic position (chromosomes 1-23; where 23 is the X chromosome), and the y-axis represents the negative logarithm (base 10) of the variant P value. The blue line indicates the genome-wide suggestive threshold (P ≤ 1E-06), while the red line indicates genome-wide significant threshold (P ≤ 5E-08). Genome-wide suggestive loci in the meta-analysis of both sexes (±500 kb of lead variant) are highlighted in green.

Figure 3.

Mendelian randomization analyses of cardiometabolic risk factors on risk of upper urinary tract infections. Forest plot of the 2-sample inverse variance–weighted Mendelian randomization analyses. Each exposure was evaluated separately for the female-only, male-only, and both-sexes analyses. The meta-analysis results from the sex-stratified analysis, which included UK Biobank and the Trøndelag Health Study (HUNT), and the analysis of both sexes, which included UK Biobank, HUNT, and Michigan Genomics Initiative, were used as the outcomes. The x-axis represents the results in odds ratio expressed as per standard deviation increase in genetically proxied levels of the exposure for continuous traits (body mass, smoking, low-density lipoprotein cholesterol, systolic blood pressure) and as per-unit increase in log odds ratio for genetically proxied type 2 diabetes mellitus liability. Abbreviations: BMI, body mass index; CI, confidence interval; LDL, low-density lipoprotein cholesterol.