Confirmation of HLA-II associations with TB susceptibility in admixed African samples

  1. Dayna Adrienne Croock
  2. Yolandi Swart
  3. Haiko Schurz
  4. Desiree C Petersen
  5. Marlo Möller
  6. Caitlin Uren  Is a corresponding author
  1. DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
  2. Centre for Bioinformatics and Computational Biology, Stellenbosch University, South Africa
5 figures, 3 tables and 5 additional files

Figures

Genome-wide ancestral proportions of all individuals in the merged dataset.

Ancestral proportions for each individual are plotted vertically with different colours representing different contributing ancestries.

Local ancestry karyograms of three admixed individuals from the SAC population.

Each admixed individual (A, B and C) has unique local ancestry patterns generated by admixture among geographically distinct ancestral population groups.

Figure 3 with 1 supplement
Log transformation of association signals obtained for KhoeSan ancestry whilst using the LAAA model on chromosome 6.

The thresholds for genome-wide significance (p-value = 5 x 10–8) and suggestive significance (p-value = 1 x 10–5) and the significance threshold for admixture mapping (p-value = 2.5 x 10–6) are shown. The four different models are represented in black (global ancestry only - GAO), blue (local ancestry effect - LAO), orange (ancestry plus allelic effect - APA), and pink (local ancestry adjusted allelic effect - LAAA).

Figure 3—figure supplement 1
QQ-plot of expected p-values and observed p-values for the association signals obtained for Khoisan ancestry located on chromosome 6.
Regional plot indicating the nearest genes in the region of the lead variant (rs3117230) observed on chromosome 6.

SNPs in linkage disequilibrium (LD) with the lead variant are coloured red/orange. The lead variant is indicated in purple. Functional protein-coding genes are coded in red and non-functional (pseudo-genes) are indicated in black.

A schematic diagram of the location of HLA-II genes associated with TB susceptibility.

Genes in red were identified by the ITHGC. Genes in blue were identified by this study.

Tables

Table 1
Suggestive associations (p-value <1e–5) for the LAAA analysis adjusting for KhoeSan local ancestry on chromosome 6.
PositionMarker nameRefAltAltFreqOR (95% CI)SEp-value (x10–6)GeneLocationImputed/typedINFO score
33075635rs3117230AG0.3700.437 (0.306; 0.624)0.1825.292HLA-DPB1IntergenicGenotypedNA
33048661rs1042151AG0.3250.437 (0.305; 0.627)0.1846.806HLA-DPB1ExonicImputed0.992
33058874rs2179920CT0.3690.445 (0.313; 0.633)0.1806.960HLA-DPB1IntergenicGenotypedNA
33072266rs2064478CT0.3710.447 (0.313; 0.637)0.1818.222HLA-DPB1IntergenicImputed1
33072729rs3130210GT0.3710.447 (0.313; 0.637)0.1818.222HLA-DPB1IntergenicImputed0.999
33073440rs2064475GA0.3710.447 (0.313; 0.637)0.1818.222HLA-DPB1IntergenicImputed1
33074348rs3117233TC0.3710.447 (0.313; 0.637)0.1818.222HLA-DPB1IntergenicImputed1
33074707rs3130213GA0.3710.447 (0.313; 0.637)0.1818.222HLA-DPB1IntergenicImputed0.970
  1. Ref, reference allele; Alt, alternate allele; AltFreq, alternate allele frequency; OR, odds ratio; SE, standard error.

Table 2
Summary of the datasets included in analysis.
DatasetGenotyping platformSelf-reported ethnicityCases/controlsReference
RSA(A)Affymetrix 500 kSAC642/91Daya et al., 2013
RSA(M)MEGA array 1.1 MSAC555/440Schurz et al., 2018; Swart et al., 2021
RSA(TANDEM)H3Africa arraySAC and Bantu-speaking African161/133Swart et al., 2022b
RSA(NCTB)H3Africa arraySAC49/111Oyageshio et al., 2023
RSA(Worcester)H3Africa arraySAC61 casesUnpublished
RSA(Xhosa)Whole genome sequencingIsiXhosa44/120Unpublished
Table 3
Ancestral populations included for global ancestry deconvolution.
PopulationnSource
European (British – GBR)401000 Genomes (1000 G) phase 3 (Auton et al., 2015)
East Asian (Chinese – CHB)401000 G phase 3
Bantu-speaking African (Yoruba – YRI)401000 G phase 3
Southeast Asian (Malaysian)38Singapore Sequencing Malay Project (SSMP) (Wong et al., 2013)
KhoeSan (Nama)33African Genome Variation Project (AGVP/ADRP) (Gurdasani et al., 2015)

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/99200/elife-99200-mdarchecklist1-v1.docx
Supplementary file 1

Summary statistics for two variants within 800 base pairs of the ITHGC lead SNP 167 (rs28383206) on chromosome 6 for the LAAA analysis adjusting for KhoeSan and Bantu-speaking African local 168 ancestry.

https://cdn.elifesciences.org/articles/99200/elife-99200-supp1-v1.xlsx
Supplementary file 2

The number of individuals and variants across all array datasets following genotype QC.

https://cdn.elifesciences.org/articles/99200/elife-99200-supp2-v1.xlsx
Supplementary file 3

Summary of the age, sex and ancestral proportions for individuals in the merged cohort.

https://cdn.elifesciences.org/articles/99200/elife-99200-supp3-v1.xlsx
Supplementary file 4

Summary statistics of the results for chromosome 6 whilst using the local ancestry adjusted allelic (LAAA) model whilst adjusting for KhoeSan ancestry.

https://cdn.elifesciences.org/articles/99200/elife-99200-supp4-v1.xlsx

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  1. Dayna Adrienne Croock
  2. Yolandi Swart
  3. Haiko Schurz
  4. Desiree C Petersen
  5. Marlo Möller
  6. Caitlin Uren
(2025)
Confirmation of HLA-II associations with TB susceptibility in admixed African samples
eLife 13:RP99200.
https://doi.org/10.7554/eLife.99200.4