| Title: | The BS variant of C4 protects against age-related loss of white matter microstructural integrity |
| Journal: | Brain |
| Published: | 6 Aug 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34358307/ |
| DOI: | https://doi.org/10.1093/brain/awab261 |
| URL: | https://academic.oup.com/brain/article-pdf/145/1/295/43246577/awab261.pdf |
| Citations: | 2 (2 in last 2 years) as of 8 Aug 2024 |
Publication 5822
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
10 Keywords
- Aged
- Aged, 80 and over
- Anisotropy
- Complement C4
- Diffusion Magnetic Resonance Imaging
- Diffusion Tensor Imaging
- Genome-Wide Association Study
- Humans
- Middle Aged
- White Matter
4 Authors
- Matthew Traylor
- Rainer Malik
- Benno Gesierich
- Martin Dichgans
Enabling scientific discoveries that improve human health