. 2024 Dec;56(12):2685-2695.

doi: 10.1038/s41588-024-01973-7. Epub 2024 Nov 11.

Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

Ciyang Wang^{1

2

3}, Chengran Yang^{1

2}, Daniel Western^{1

2

3}, Muhammad Ali^{1

2}, Yueyao Wang^{1

2}, Chia-Ling Phuah^{2

4}, John Budde^{1

2}, Lihua Wang^{1

2}, Priyanka Gorijala^{1

2}, Jigyasha Timsina^{1

2}, Agustin Ruiz^{5

6

7}, Pau Pastor^{8

9}, Maria Victoria Fernandez^{1

2}; Dominantly Inherited Alzheimer Network (DIAN); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Daniel J Panyard¹⁰, Corinne D Engelman¹¹, Yuetiva Deming¹², Merce Boada^{5

6}, Amanda Cano^{5

6}, Pablo Garcia-Gonzalez⁵, Neill R Graff-Radford¹³, Hiroshi Mori^{14

15}, Jae-Hong Lee¹⁶, Richard J Perrin^{17

18

19}, Laura Ibanez^{1

2

18}, Yun Ju Sung^{1

2

20}, Carlos Cruchaga^{21

22

23}

Collaborators, Affiliations

Collaborators

Richard Perrin

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
³ Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Division of Neurocritical Care, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
⁵ Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
⁶ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain.
⁷ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
⁸ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Spain.
⁹ The Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain.
¹⁰ Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹¹ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹⁴ Department of Clinical Neuroscience, Faculty of Medicine, Osaka Metropolitan University, Osaka, Japan.
¹⁵ Nagaoka Sutoku University, Niigata, Japan.
¹⁶ University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
¹⁷ Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, USA.
¹⁸ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
²⁰ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
²¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²³ Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.

PMID: 39528826
PMCID: PMC12090064 (available on 2025-12-01)
DOI: 10.1038/s41588-024-01973-7

Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

Ciyang Wang et al. Nat Genet. 2024 Dec.

. 2024 Dec;56(12):2685-2695.

doi: 10.1038/s41588-024-01973-7. Epub 2024 Nov 11.

Authors

Collaborators

Richard Perrin

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
³ Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Division of Neurocritical Care, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
⁵ Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
⁶ CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain.
⁷ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
⁸ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Spain.
⁹ The Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain.
¹⁰ Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹¹ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹⁴ Department of Clinical Neuroscience, Faculty of Medicine, Osaka Metropolitan University, Osaka, Japan.
¹⁵ Nagaoka Sutoku University, Niigata, Japan.
¹⁶ University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
¹⁷ Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, USA.
¹⁸ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
²⁰ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
²¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²³ Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.

PMID: 39528826
PMCID: PMC12090064 (available on 2025-12-01)
DOI: 10.1038/s41588-024-01973-7

Abstract

Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite-trait associations, such as glycerophosphocholines with Alzheimer's disease, O-sulfo-L-tyrosine with Parkinson's disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits.

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Conflict of interest statement

Competing interests: C.C. has received research support from GSK and EISAI and is a member of the advisory board of Circular Genomics and owns stocks. A.R. and M.B. have received research support from Grifols, Roche, Araclon and Janssen. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. All other authors have no conflict of interest.

Update of

Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness.
Wang C, Western D, Yang C, Ali M, Wang L, Gorijala P, Timsina J, Ruiz A, Pastor P, Fernandez M, Panyard D, Engelman C, Deming Y, Boada M, Cano A, García-González P, Graff-Radford N, Mori H, Lee JH, Perrin R, Sung YJ; Dominantly Inherited Alzheimer Network (DIAN); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Cruchaga C. Wang C, et al. Res Sq [Preprint]. 2023 Jun 9:rs.3.rs-2923409. doi: 10.21203/rs.3.rs-2923409/v1. Res Sq. 2023. Update in: Nat Genet. 2024 Dec;56(12):2685-2695. doi: 10.1038/s41588-024-01973-7. PMID: 37333177 Free PMC article. Updated. Preprint.

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Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

Collaborators

Affiliations

Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Update of

References

Methods-only References

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