The BS variant of C4 protects against age-related loss of white matter microstructural integrity.
Brain. 2021 Aug 6:awab261. doi: 10.1093/brain/awab261. Epub ahead of print. PMID: 34358307.
|Authors/Editors:||Traylor M, Malik R, Gesierich B, Dichgans M.|
Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia, and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a GWAS of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity, MD; and fractional anisotropy, FA) in up to 31,128 individuals from UK Biobank (age 45–81 years) based on a 2 degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP x age effects. We identified 18 loci that were associated at genome-wide significance with either MD (N = 16) or FA (N = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both MD (best SNP: 6:28866209_TTTTG_T, beta(SE)=-0.069(0.009); 2df p = 6.5x10−15) and FA (best SNP: rs3129787, beta(SE)=-0.056(0.008); 2df p = 3.5x10−12). Of the imputed HLA alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant (for MD: beta(SE)=-0.070(0.010); p = 2.7x10−11; for FA: beta(SE)=-0.054(0.011); p = 1.6x10−7). After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older subjects (age ≥ 65; interaction p = 0.0019 (MD), p = 0.015 (FA)) and in subjects without a history of smoking (interaction p = 0.00093 (MD), p = 0.021 (FA)). Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.