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@ARTICLE{Ahmad:270184,
      author       = {Ahmad, Shahzad and Imtiaz, Mohammed Aslam and Mishra,
                      Aniket and Wang, Ruiqi and Herrera-Rivero, Marisol and Bis,
                      Joshua C and Fornage, Myriam and Roshchupkin, Gennady and
                      Hofer, Edith and Logue, Mark and Longstreth, WT and Xia, Rui
                      and Bouteloup, Vincent and Mosley, Thomas and Launer, Lenore
                      and Khalil, Michael and Kuhle, Jens and Rissman, Robert A.
                      and Chene, Genevieve and Dufouil, Carole and Djoussé, Luc
                      and Lyons, Michael J. and Mukamal, Kenneth J. and Kremen,
                      William S. and Franz, Carol E. and Schmidt, Reinhold and
                      Debette, Stephanie and Breteler, Monique M. B. and Berger,
                      Klaus and Yang, Qiong and Seshadri, Sudha and Aziz, N. Ahmad
                      and Ghanbari, Mohsen and Ikram, M. Arfan},
      title        = {{G}enome-wide {A}ssociation {S}tudy {M}eta-analysis of
                      {N}eurofilament light ({N}f{L}) levels in blood reveals
                      novel loci related to neurodegeneration},
      reportid     = {DZNE-2024-00755},
      year         = {2022},
      abstract     = {Background: 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 and its genetic correlation with neurological
                      traits could therefore provide new insights into shared
                      molecular mechanisms underlying neurodegenerative
                      disorders.Methods: To identify the genetic variations
                      underlying blood NfL levels, we conducted an
                      ancestry-specific meta-analyses of genome-wide association
                      studies (GWAS) based on 18,532 participants from 11 cohorts
                      of European and 1142 participants (3 cohorts) of
                      African-American ancestry. In the post-GWAS analyses, we
                      performed expression quantitative trait loci (eQTL)
                      analysis, LD-regression, and genetic risk score (GRS)
                      association analysis with neurological traits.Results: In
                      the European ancestry GWAS meta-analysis, we identified two
                      genome-wide significant (P < 5x10−8) loci at 16p12 (UMOD),
                      and 17q24 (SLC39A11). In the African-American ancestry GWAS
                      meta-analysis, we identified three novel loci at 1q43
                      (FMN2), 12q14, and 12q21. Genetic correlation based on the
                      European ancestry meta-analysis with neurological traits
                      showed a strong genetic correlation of NfL with
                      Alzheimer’s disease(AD) (rg = 0.32, P = 1.74x10−6),
                      total-tau (rg = 2.01, P = 1.03x10−6), amyloid-beta
                      (Aβ)-40 (rg = 0.80, P = 6.92x10−6), and Aβ-42 (rg =
                      1.03, P = 4.39x10−5). A higher genetic risk score based on
                      NfL-associated genetic variants was also related to
                      increased plasma levels of total-tau (P = 1.97x10−4),
                      Aβ-40 (P = 2.24x10−5), Aβ-42 (P = 2.92x10−4) in the
                      Rotterdam Study.Conclusion: This large-scale GWAS
                      meta-analysis revealed multiple novel genetic loci of NFL
                      levels in blood in participants from European and
                      African-American ancestry. Significant genetic correlation
                      of genes underlying NfL with AD, Aβ-42, and total-tau may
                      indicate a common underlying pathway of neurodegeneration.},
      cin          = {AG Aziz / AG Breteler},
      cid          = {I:(DE-2719)5000071 / I:(DE-2719)1012001},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)25},
      doi          = {10.1101/2022.12.14.22283446},
      url          = {https://pub.dzne.de/record/270184},
}