000270184 001__ 270184
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000270184 0247_ $$2doi$$a10.1101/2022.12.14.22283446
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000270184 037__ $$aDZNE-2024-00755
000270184 1001_ $$00000-0002-8658-3790$$aAhmad, Shahzad$$b0$$eFirst author
000270184 245__ $$aGenome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration
000270184 260__ $$c2022
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000270184 520__ $$aBackground: 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.
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000270184 7001_ $$0P:(DE-2719)9002347$$aImtiaz, Mohammed Aslam$$b1$$eFirst author
000270184 7001_ $$0P:(DE-HGF)0$$aMishra, Aniket$$b2
000270184 7001_ $$0P:(DE-HGF)0$$aWang, Ruiqi$$b3
000270184 7001_ $$0P:(DE-HGF)0$$aHerrera-Rivero, Marisol$$b4
000270184 7001_ $$0P:(DE-HGF)0$$aBis, Joshua C$$b5
000270184 7001_ $$0P:(DE-HGF)0$$aFornage, Myriam$$b6
000270184 7001_ $$0P:(DE-HGF)0$$aRoshchupkin, Gennady$$b7
000270184 7001_ $$0P:(DE-HGF)0$$aHofer, Edith$$b8
000270184 7001_ $$0P:(DE-HGF)0$$aLogue, Mark$$b9
000270184 7001_ $$0P:(DE-HGF)0$$aLongstreth, WT$$b10
000270184 7001_ $$0P:(DE-HGF)0$$aXia, Rui$$b11
000270184 7001_ $$0P:(DE-HGF)0$$aBouteloup, Vincent$$b12
000270184 7001_ $$0P:(DE-HGF)0$$aMosley, Thomas$$b13
000270184 7001_ $$0P:(DE-HGF)0$$aLauner, Lenore$$b14
000270184 7001_ $$0P:(DE-HGF)0$$aKhalil, Michael$$b15
000270184 7001_ $$0P:(DE-HGF)0$$aKuhle, Jens$$b16
000270184 7001_ $$0P:(DE-HGF)0$$aRissman, Robert A.$$b17
000270184 7001_ $$0P:(DE-HGF)0$$aChene, Genevieve$$b18
000270184 7001_ $$0P:(DE-HGF)0$$aDufouil, Carole$$b19
000270184 7001_ $$0P:(DE-HGF)0$$aDjoussé, Luc$$b20
000270184 7001_ $$0P:(DE-HGF)0$$aLyons, Michael J.$$b21
000270184 7001_ $$0P:(DE-HGF)0$$aMukamal, Kenneth J.$$b22
000270184 7001_ $$0P:(DE-HGF)0$$aKremen, William S.$$b23
000270184 7001_ $$0P:(DE-HGF)0$$aFranz, Carol E.$$b24
000270184 7001_ $$0P:(DE-2719)9000857$$aSchmidt, Reinhold$$b25
000270184 7001_ $$0P:(DE-HGF)0$$aDebette, Stephanie$$b26
000270184 7001_ $$0P:(DE-2719)2810403$$aBreteler, Monique M. B.$$b27
000270184 7001_ $$0P:(DE-HGF)0$$aBerger, Klaus$$b28
000270184 7001_ $$0P:(DE-HGF)0$$aYang, Qiong$$b29
000270184 7001_ $$0P:(DE-HGF)0$$aSeshadri, Sudha$$b30
000270184 7001_ $$0P:(DE-2719)2812578$$aAziz, N. Ahmad$$b31$$eLast author
000270184 7001_ $$0P:(DE-HGF)0$$aGhanbari, Mohsen$$b32$$eLast author
000270184 7001_ $$0P:(DE-HGF)0$$aIkram, M. Arfan$$b33$$eLast author
000270184 773__ $$a10.1101/2022.12.14.22283446
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