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Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration.

Ahmad S, Imtiaz MA, Mishra A et al.

39251807 PubMed ID
GWAS Study Type
18532 Participants
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Chapter I

Publication Details

Comprehensive information about this research publication

Authors

AS
Ahmad S
IM
Imtiaz MA
MA
Mishra A
WR
Wang R
HM
Herrera-Rivero M
BJ
Bis JC
FM
Fornage M
RG
Roshchupkin G
HE
Hofer E
LM
Logue M
LW
Longstreth WT
XR
Xia R
BV
Bouteloup V
MT
Mosley T
LL
Launer LJ
KM
Khalil M
KJ
Kuhle J
RR
Rissman RA
CG
Chene G
DC
Dufouil C
DL
Djoussé L
LM
Lyons MJ
MK
Mukamal KJ
KW
Kremen WS
FC
Franz CE
SR
Schmidt R
DS
Debette S
BM
Breteler MMB
BK
Berger K
YQ
Yang Q
SS
Seshadri S
AN
Aziz NA
GM
Ghanbari M
IM
Ikram MA
Chapter II

Abstract

Summary of the research findings

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer's disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

18,532 European ancestry individuals

Chapter III

Study Statistics

Key metrics and study information

18532
Total Participants
GWAS
Study Type
No
Replicated
European, African American or Afro-Caribbean
Ancestry
Canada, Netherlands, Austria, U.S., France, Germany
Recruitment Country
Chapter IV

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