Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum
IntroductionThe measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of individuals without neurological conditions.MethodsWe performed a discovery genome-wide as...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1145737/full |
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| author | Marisol Herrera-Rivero Edith Hofer Edith Hofer Aleksandra Maceski David Leppert Pascal Benkert Jens Kuhle Reinhold Schmidt Michael Khalil Heinz Wiendl Monika Stoll Monika Stoll Klaus Berger |
| author_facet | Marisol Herrera-Rivero Edith Hofer Edith Hofer Aleksandra Maceski David Leppert Pascal Benkert Jens Kuhle Reinhold Schmidt Michael Khalil Heinz Wiendl Monika Stoll Monika Stoll Klaus Berger |
| author_sort | Marisol Herrera-Rivero |
| collection | DOAJ |
| description | IntroductionThe measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of individuals without neurological conditions.MethodsWe performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study (N = 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort (N = 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.ResultsOur discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 × 10−5). After meta-analysis, 7 loci were suggestive of an association with sNfL. Genotype-specific differences in sNfL were observed for the lead variants of meta-analysis loci (rs34523114, rs114956339, rs529938, rs73198093, rs34372929, rs10982883, and rs1842909) in BiDirect participants. We identified potential associations in meta-analysis loci with markers of inflammation and renal function. At least 6 protein-coding genes (ACTG2, TPRKB, DMXL1, COL23A1, NAT1, and RIMS2) were suggested as genetic factors contributing to baseline sNfL levels.DiscussionOur findings suggest that polygenic regulation of neuronal processes, inflammation, metabolism and clearance modulate the variability of NfL in the circulation. These could aid in the interpretation of sNfL measurements in a personalized manner. |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-10T05:22:42Z |
| publishDate | 2023-03-01 |
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| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-a623c15edc0b429eab0208d30c500a4b2023-03-08T05:55:11ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-03-011410.3389/fneur.2023.11457371145737Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serumMarisol Herrera-Rivero0Edith Hofer1Edith Hofer2Aleksandra Maceski3David Leppert4Pascal Benkert5Jens Kuhle6Reinhold Schmidt7Michael Khalil8Heinz Wiendl9Monika Stoll10Monika Stoll11Klaus Berger12Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, GermanyDepartment of Neurology, Medical University of Graz, Graz, AustriaInstitute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, AustriaNeurologic Clinic and Polyclinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital of Basel, Basel, SwitzerlandNeurologic Clinic and Polyclinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital of Basel, Basel, SwitzerlandClinical Trial Unit, Department of Clinical Research, University Hospital of Basel, Basel, SwitzerlandNeurologic Clinic and Polyclinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital of Basel, Basel, SwitzerlandDepartment of Neurology, Medical University of Graz, Graz, AustriaDepartment of Neurology, Medical University of Graz, Graz, AustriaDepartment of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, GermanyDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, GermanyDepartment of Biochemistry, Genetic Epidemiology and Statistical Genetics, Maastricht University, Maastricht, NetherlandsInstitute of Epidemiology and Social Medicine, University of Münster, Münster, GermanyIntroductionThe measurement of neurofilament light chain (NfL) in blood is a promising biomarker of neurological injury and disease. We investigated the genetic factors that underlie serum NfL levels (sNfL) of individuals without neurological conditions.MethodsWe performed a discovery genome-wide association study (GWAS) of sNfL in participants of the German BiDirect Study (N = 1,899). A secondary GWAS for meta-analysis was performed in a small Austrian cohort (N = 287). Results from the meta-analysis were investigated in relation with several clinical variables in BiDirect.ResultsOur discovery GWAS identified 12 genomic loci at the suggestive threshold ((p < 1 × 10−5). After meta-analysis, 7 loci were suggestive of an association with sNfL. Genotype-specific differences in sNfL were observed for the lead variants of meta-analysis loci (rs34523114, rs114956339, rs529938, rs73198093, rs34372929, rs10982883, and rs1842909) in BiDirect participants. We identified potential associations in meta-analysis loci with markers of inflammation and renal function. At least 6 protein-coding genes (ACTG2, TPRKB, DMXL1, COL23A1, NAT1, and RIMS2) were suggested as genetic factors contributing to baseline sNfL levels.DiscussionOur findings suggest that polygenic regulation of neuronal processes, inflammation, metabolism and clearance modulate the variability of NfL in the circulation. These could aid in the interpretation of sNfL measurements in a personalized manner.https://www.frontiersin.org/articles/10.3389/fneur.2023.1145737/fullGWASneurofilament light chainserum biomarkersneuropathologygenetics |
| spellingShingle | Marisol Herrera-Rivero Edith Hofer Edith Hofer Aleksandra Maceski David Leppert Pascal Benkert Jens Kuhle Reinhold Schmidt Michael Khalil Heinz Wiendl Monika Stoll Monika Stoll Klaus Berger Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum Frontiers in Neurology GWAS neurofilament light chain serum biomarkers neuropathology genetics |
| title | Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| title_full | Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| title_fullStr | Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| title_full_unstemmed | Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| title_short | Evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| title_sort | evidence of polygenic regulation of the physiological presence of neurofilament light chain in human serum |
| topic | GWAS neurofilament light chain serum biomarkers neuropathology genetics |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1145737/full |
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