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However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive.<\/jats:p><jats:p>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\u201381 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP \u00d7 Age effects.<\/jats:p><jats:p>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) = \u22120.069 (0.009); 2df P = 6.5 \u00d7 10\u221215] and fractional anisotropy [best SNP: rs3129787, beta (SE) = \u22120.056 (0.008); 2df P = 3.5 \u00d7 10\u221212]. 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) = \u22120.070 (0.010); P = 2.7 \u00d7 10\u221211; for fractional anisotropy: beta (SE) = \u22120.054 (0.011); P = 1.6 \u00d7 10\u22127]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age \u2265 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)].<\/jats:p><jats:p>Taken together, our findings demonstrate a role of the complement system and of gene\u2013environment interactions in age-related loss of white matter microstructural integrity.<\/jats:p>","DOI":"10.1093\/brain\/awab261","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T11:44:28Z","timestamp":1628077468000},"page":"295-304","source":"Crossref","is-referenced-by-count":5,"title":["The BS variant of C4 protects against age-related loss of white matter microstructural integrity"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6624-8621","authenticated-orcid":false,"given":"Matthew","family":"Traylor","sequence":"first","affiliation":[{"name":"Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK"},{"name":"The Barts Heart Centre and NIHR Barts Biomedical Research Centre\u2014Barts Health NHS Trust, The William Harvey Research Institute, Queen Mary University London, London, UK"},{"name":"Novo Nordisk Research Centre Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-2520","authenticated-orcid":false,"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benno","family":"Gesierich","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany"},{"name":"German Centre for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"2022040311310845400_awab261-B1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.neurobiolaging.2019.08.021","article-title":"Association of white matter microstructural integrity with cognition 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