The BS variant of C4 protects against age-related loss of white matter microstructural integrity

Abstract

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 genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45–81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects. We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (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 mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = −0.069 (0.009); 2df P = 6.5 × 10⁻¹⁵] and fractional anisotropy [best SNP: rs3129787, beta (SE) = −0.056 (0.008); 2df P = 3.5 × 10⁻¹²]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = −0.070 (0.010); P = 2.7 × 10⁻¹¹; for fractional anisotropy: beta (SE) = −0.054 (0.011); P = 1.6 × 10⁻⁷]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)]. 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.