HLA region

For post-GWAS analyses, we often exclude the HLA (Human Leukocyte Antigen) region due to its exceptional complexity of linkage disequilibrium (LD). The HLA region on chromosome 6 contains the most polymorphic genes in the human genome, with extensive LD patterns that can confound association analyses.

In GWASLab, exclude_hla() is designed to remove variants in the extended MHC (xMHC) region by default.

Default exclusion range: chr6:25-34 Mb

By default, exclude_hla() removes variants in chr6:25,000,000 ~ 34,000,000 (25-34 Mb) for both hg19 and hg38.

Why 25-34 Mb instead of exact gene boundaries?

The actual gene boundaries for the extended MHC region are:

• xMHC (HIST1H2AA ~ RPL12P1):
• hg38: 25,726,063 ~ 33,400,644
• hg19: 25,726,291 ~ 33,368,421

However, GWASLab uses the simplified 25-34 Mb range for several practical reasons:

1. Safety margin: The rounded boundaries ensure complete coverage of the complex LD region, accounting for:
2. Variants near gene boundaries that may still be in strong LD
3. Coordinate differences between genome builds

4. Edge cases where variants might be slightly outside exact gene boundaries

5. Consistency: The same range (25-34 Mb) works for both hg19 and hg38, simplifying usage and avoiding build-specific confusion

6. Standard practice: Many GWAS analyses and tools use rounded boundaries (e.g., 25-34 Mb) for HLA exclusion, making results more comparable across studies

7. Practical simplicity: Round numbers are easier to remember, communicate, and use in analyses

8. Comprehensive coverage: The 25-34 Mb range fully encompasses the extended MHC region while providing a conservative buffer zone

Region definitions

Extended MHC (xMHC) region

The extended MHC region spans from HIST1H2AA to RPL12P1, covering approximately 7.6 Mb.

Reference: Horton, R., Wilming, L., Rand, V., Lovering, R. C., Bruford, E. A., Khodiyar, V. K., ... & Beck, S. (2004). Gene map of the extended human MHC. Nature Reviews Genetics, 5(12), 889-899.

Exact gene boundaries: - Start: HIST1H2AA - End: RPL12P1 - hg38: 25,726,063 ~ 33,400,644 - hg19: 25,726,291 ~ 33,368,421 - T2T-CHM13v2.0: 25,591,841 ~ 33,222,006

GWASLab default: chr6:25,000,000 ~ 34,000,000 (mode="xmhc")

Classical HLA region

The classical HLA region spans from GABBR1 to KIFC1, covering approximately 3.78 Mb.

Reference: Shiina, T., Hosomichi, K., Inoko, H., & Kulski, J. K. (2009). The HLA genomic loci map: expression, interaction, diversity and disease. Journal of human genetics, 54(1), 15-39.

Exact gene boundaries: - Start: GABBR1 - End: KIFC1 - hg38: 29,602,238 ~ 33,409,896 - hg19: 29,570,015 ~ 33,377,673 - T2T-CHM13v2.0: 29,476,949 ~ 33,231,258

GWASLab default: chr6:29,500,000 ~ 33,500,000 (mode="hla" or mode="mhc")

Usage

# Exclude extended MHC region (default, 25-34 Mb)
mysumstats.exclude_hla()

# Exclude classical HLA region only (29.5-33.5 Mb)
mysumstats.exclude_hla(mode="hla")

# Custom range
mysumstats.exclude_hla(lower=25000000, upper=34000000)

# Specify genome build (uses build-specific ranges)
mysumstats.exclude_hla(build="38", mode="xmhc")