Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease

Daniel Western; Jigyasha Timsina; Lihua Wang; Ciyang Wang; Chengran Yang; Bridget Phillips; Yueyao Wang; Menghan Liu; Muhammad Ali; Aleksandra Beric; Priyanka Gorijala; Pat Kohlfeld; John Budde; Allan I Levey; John C Morris; Richard J Perrin; Agustin Ruiz; Marta Marquié; Mercè Boada; Itziar de Rojas; Jarod Rutledge; Hamilton Oh; Edward N Wilson; Yann Le Guen; Lianne M Reus; Betty Tijms; Pieter Jelle Visser; Sven J van der Lee; Yolande A L Pijnenburg; Charlotte E Teunissen; Marta Del Campo Milan; Ignacio Alvarez; Miquel Aguilar; Dominantly Inherited Alzheimer Network (DIAN); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Michael D Greicius; Pau Pastor; David J Pulford; Laura Ibanez; Tony Wyss-Coray; Yun Ju Sung; Carlos Cruchaga

doi:10.1038/s41588-024-01972-8

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease

Nat Genet. 2024 Nov 11. doi: 10.1038/s41588-024-01972-8. Online ahead of print.

Authors

Daniel Western^{1

2

3}, Jigyasha Timsina^{1

2}, Lihua Wang^{1

2}, Ciyang Wang^{1

2

3}, Chengran Yang^{1

2}, Bridget Phillips^{1

2

3}, Yueyao Wang^{1

2}, Menghan Liu^{1

2}, Muhammad Ali^{1

2}, Aleksandra Beric^{1

2}, Priyanka Gorijala^{1

2}, Pat Kohlfeld^{1

2}, John Budde^{1

2}, Allan I Levey⁴, John C Morris⁵, Richard J Perrin^{5

6

7}, Agustin Ruiz^{8

9

10}, Marta Marquié^{8

9}, Mercè Boada^{8

9}, Itziar de Rojas^{8

9}, Jarod Rutledge¹¹, Hamilton Oh¹¹, Edward N Wilson^{11

12}, Yann Le Guen^{12

13}, Lianne M Reus^{14

15}, Betty Tijms^{14

15}, Pieter Jelle Visser^{14

15

16}, Sven J van der Lee^{14

15

17}, Yolande A L Pijnenburg^{14

15}, Charlotte E Teunissen¹⁸, Marta Del Campo Milan^{19

20}, Ignacio Alvarez²¹, Miquel Aguilar²¹; Dominantly Inherited Alzheimer Network (DIAN); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Michael D Greicius^{11

12}, Pau Pastor^{21

22}, David J Pulford²³, Laura Ibanez^{1

2

5}, Tony Wyss-Coray¹¹, Yun Ju Sung^{1

2

24}, Carlos Cruchaga^{25

26

27

28}

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 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA.
⁸ ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
⁹ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁰ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.
¹¹ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
¹² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
¹³ Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁴ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
¹⁵ Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
¹⁶ Department of Psychiatry, Maastricht University, Maastricht, the Netherlands.
¹⁷ Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
¹⁸ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, the Netherlands.
¹⁹ Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo CEU, CEU Universities, Madrid, Spain.
²⁰ Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
²¹ Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain.
²² Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and the Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
²³ Medicines R&D, GlaxoSmithKline, Stevenage, UK.
²⁴ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
²⁵ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²⁶ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.
²⁷ Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
²⁸ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.

PMID: 39528825
DOI: 10.1038/s41588-024-01972-8

Abstract

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

Abstract

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