The genetic regulation of protein expression in cerebrospinal fluid
Abstract Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations betwee...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216359 |
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| author | Oskar Hansson Atul Kumar Shorena Janelidze Erik Stomrud Philip S Insel Kaj Blennow Henrik Zetterberg Eric Fauman Åsa K Hedman Michael W Nagle Christopher D Whelan Denis Baird Anders Mälarstig Niklas Mattsson‐Carlgren |
| author_facet | Oskar Hansson Atul Kumar Shorena Janelidze Erik Stomrud Philip S Insel Kaj Blennow Henrik Zetterberg Eric Fauman Åsa K Hedman Michael W Nagle Christopher D Whelan Denis Baird Anders Mälarstig Niklas Mattsson‐Carlgren |
| author_sort | Oskar Hansson |
| collection | DOAJ |
| description | Abstract Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis‐pQTLs and 59 trans‐pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF‐specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP‐10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP‐10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome. |
| format | Article |
| id | doaj-art-4174b4e6116f45eb86dccf005c92af0b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-4174b4e6116f45eb86dccf005c92af0b2025-08-24T11:43:32ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-12-0115111610.15252/emmm.202216359The genetic regulation of protein expression in cerebrospinal fluidOskar Hansson0Atul Kumar1Shorena Janelidze2Erik Stomrud3Philip S Insel4Kaj Blennow5Henrik Zetterberg6Eric Fauman7Åsa K Hedman8Michael W Nagle9Christopher D Whelan10Denis Baird11Anders Mälarstig12Niklas Mattsson‐Carlgren13Clinical Memory Research Unit, Faculty of Medicine, Lund UniversityClinical Memory Research Unit, Faculty of Medicine, Lund UniversityClinical Memory Research Unit, Faculty of Medicine, Lund UniversityClinical Memory Research Unit, Faculty of Medicine, Lund UniversityClinical Memory Research Unit, Faculty of Medicine, Lund UniversityClinical Neurochemistry Laboratory, Sahlgrenska University HospitalClinical Neurochemistry Laboratory, Sahlgrenska University HospitalInternal Medicine Research Unit, Pfizer Worldwide Research, Development and MedicalPfizer Worldwide Research, Development and MedicalNeurogenomics, Genetics‐Guided Dementia Discovery, Eisai, IncTranslational Biology, Biogen Research & Development, Biogen IncDepartment of Neurology, Skåne University Hospital, Lund UniversityPfizer Worldwide Research, Development and MedicalClinical Memory Research Unit, Faculty of Medicine, Lund UniversityAbstract Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis‐pQTLs and 59 trans‐pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF‐specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP‐10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP‐10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.https://doi.org/10.15252/emmm.202216359biomarkerscerebrospinal fluidgenetic regulationMendelian randomizationpQTL |
| spellingShingle | Oskar Hansson Atul Kumar Shorena Janelidze Erik Stomrud Philip S Insel Kaj Blennow Henrik Zetterberg Eric Fauman Åsa K Hedman Michael W Nagle Christopher D Whelan Denis Baird Anders Mälarstig Niklas Mattsson‐Carlgren The genetic regulation of protein expression in cerebrospinal fluid EMBO Molecular Medicine biomarkers cerebrospinal fluid genetic regulation Mendelian randomization pQTL |
| title | The genetic regulation of protein expression in cerebrospinal fluid |
| title_full | The genetic regulation of protein expression in cerebrospinal fluid |
| title_fullStr | The genetic regulation of protein expression in cerebrospinal fluid |
| title_full_unstemmed | The genetic regulation of protein expression in cerebrospinal fluid |
| title_short | The genetic regulation of protein expression in cerebrospinal fluid |
| title_sort | genetic regulation of protein expression in cerebrospinal fluid |
| topic | biomarkers cerebrospinal fluid genetic regulation Mendelian randomization pQTL |
| url | https://doi.org/10.15252/emmm.202216359 |
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