TY - JOUR
T1 - Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration
AU - Ahmad, Shahzad
AU - Imtiaz, Mohammad Aslam
AU - Mishra, Aniket
AU - Wang, Ruiqi
AU - Herrera-Rivero, Marisol
AU - Bis, Joshua C.
AU - Fornage, Myriam
AU - Roshchupkin, Gennady
AU - Hofer, Edith
AU - Logue, Mark
AU - Longstreth, W. T.
AU - Xia, Rui
AU - Bouteloup, Vincent
AU - Mosley, Thomas
AU - Launer, Lenore J.
AU - Khalil, Michael
AU - Kuhle, Jens
AU - Rissman, Robert A.
AU - Chene, Genevieve
AU - Dufouil, Carole
AU - Djoussé, Luc
AU - Lyons, Michael J.
AU - Mukamal, Kenneth J.
AU - Kremen, William S.
AU - Franz, Carol E.
AU - Schmidt, Reinhold
AU - Debette, Stephanie
AU - Breteler, Monique M.B.
AU - Berger, Klaus
AU - Yang, Qiong
AU - Seshadri, Sudha
AU - Aziz, N. Ahmad
AU - Ghanbari, Mohsen
AU - Ikram, M. Arfan
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85203307693&partnerID=8YFLogxK
U2 - 10.1038/s42003-024-06804-3
DO - 10.1038/s42003-024-06804-3
M3 - Article
C2 - 39251807
AN - SCOPUS:85203307693
SN - 2399-3642
VL - 7
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1103
ER -