PMID- 34358307
OWN - NLM
STAT- MEDLINE
DCOM- 20220401
LR  - 20220627
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Linking)
VI  - 145
IP  - 1
DP  - 2022 Mar 29
TI  - The BS variant of C4 protects against age-related loss of white matter 
      microstructural integrity.
PG  - 295-304
LID - 10.1093/brain/awab261 [doi]
AB  - 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.
CI  - (c) The Author(s) (2021). Published by Oxford University Press on behalf of the 
      Guarantors of Brain. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Traylor, Matthew
AU  - Traylor M
AUID- ORCID: 0000-0001-6624-8621
AD  - Clinical Pharmacology, William Harvey Research Institute, Queen Mary University 
      of London, London, UK.
AD  - The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS 
      Trust, The William Harvey Research Institute, Queen Mary University London, 
      London, UK.
AD  - Novo Nordisk Research Centre Oxford, Oxford, UK.
FAU - Malik, Rainer
AU  - Malik R
AUID- ORCID: 0000-0001-9212-2520
AD  - Institute for Stroke and Dementia Research (ISD), University Hospital, LMU 
      Munich, Munich, Germany.
FAU - Gesierich, Benno
AU  - Gesierich B
AD  - Institute for Stroke and Dementia Research (ISD), University Hospital, LMU 
      Munich, Munich, Germany.
FAU - Dichgans, Martin
AU  - Dichgans M
AD  - Institute for Stroke and Dementia Research (ISD), University Hospital, LMU 
      Munich, Munich, Germany.
AD  - German Centre for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
AD  - Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Complement C4)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Anisotropy
MH  - Complement C4/*metabolism
MH  - Diffusion Magnetic Resonance Imaging
MH  - Diffusion Tensor Imaging
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Middle Aged
MH  - *White Matter/diagnostic imaging
OTO - NOTNLM
OT  - complement
OT  - genetics
OT  - white matter microstructure
EDAT- 2021/08/07 06:00
MHDA- 2022/04/02 06:00
CRDT- 2021/08/06 17:23
PHST- 2021/02/23 00:00 [received]
PHST- 2021/05/12 00:00 [revised]
PHST- 2021/06/14 00:00 [accepted]
PHST- 2021/08/07 06:00 [pubmed]
PHST- 2022/04/02 06:00 [medline]
PHST- 2021/08/06 17:23 [entrez]
AID - 6343447 [pii]
AID - 10.1093/brain/awab261 [doi]
PST - ppublish
SO  - Brain. 2022 Mar 29;145(1):295-304. doi: 10.1093/brain/awab261.