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Traylor, Matthew; Malik, Rainer; Gesierich, Benno and Dichgans, Martin ORCID logoORCID: https://orcid.org/0000-0002-0654-387X (2021): The BS variant of C4 protects against age-related loss of white matter microstructural integrity. In: Brain, Vol. 145, No. 1: pp. 295-304 [PDF, 891kB]


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 x 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 x 10(-15)] and fractional anisotropy [best SNP: rs3129787, beta (SE) = -0.056 (0.008);2df P = 3.5 x 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 x 10(-11);for fractional anisotropy: beta (SE) = -0.054 (0.011);P = 1.6 x 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.

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