The genetic landscape of neuro-related proteins in human plasma

Linda Repetto^#^{1

2

3

4}, Jiantao Chen^#^{1

2

5}, Zhijian Yang^#^{1

2

5

6}, Ranran Zhai^#^{1

2

5

6}, Paul R H J Timmers^{3

7}, Xiao Feng^{2

5}, Ting Li^{1

2

5}, Yue Yao^{2

5}, Denis Maslov⁸, Anna Timoshchuk⁸, Fengyu Tu¹, Emma L Twait⁹, Sebastian May-Wilson³, Marisa D Muckian³, Bram P Prins¹⁰, Grace Png^{11

12}, Charles Kooperberg¹³, Åsa Johansson¹⁴, Robert F Hillary¹⁵, Eleanor Wheeler¹⁶, Lu Pan⁶, Yazhou He¹⁷, Sofia Klasson¹⁸, Shahzad Ahmad¹⁹, James E Peters²⁰, Arthur Gilly¹¹, Maria Karaleftheri²¹, Emmanouil Tsafantakis²², Jeffrey Haessler¹³, Ulf Gyllensten¹⁴, Sarah E Harris²³, Nicholas J Wareham¹⁶, Andreas Göteson²⁴, Cecilia Lagging^{18

25}, Mohammad Arfan Ikram¹⁹, Cornelia M van Duijn¹⁹, Christina Jern^{18

25}, Mikael Landén^{6

24}, Claudia Langenberg^{16

26

27}, Ian J Deary²³, Riccardo E Marioni¹⁵, Stefan Enroth¹⁴, Alexander P Reiner²⁸, George Dedoussis²⁹, Eleftheria Zeggini^{11

30}, Sodbo Sharapov^{8

31}, Yurii S Aulchenko^{8

32}, Adam S Butterworth^{10

33

34

35

36

37}, Anders Mälarstig^{6

38}, James F Wilson^#^{3

7}, Pau Navarro^#^{3

7}, Xia Shen^#^{39

40

41

42

43}

Affiliations

¹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
² Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
³ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁴ Health Data Science Centre, Fondazione Human Technopole, Milan, Italy.
⁵ State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, China.
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁸ MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia.
⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.
¹⁰ BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹¹ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹² Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
¹⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁷ Department of Epidemiology and Medical Statistics, Division of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
¹⁸ Institute of Biomedicine, Department of Laboratory Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁹ Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
²⁰ Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
²¹ Echinos Medical Centre, Echinos, Greece.
²² Anogia Medical Centre, Anogia, Greece.
²³ Lothian Birth Cohorts, University of Edinburgh, Edinburgh, UK.
²⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁵ Department of Clinical Genetics and Genomics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁶ Computational Medicine, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany.
²⁷ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
²⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center and Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁹ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece.
³⁰ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine and Health, Munich, Germany.
³¹ Biostatistics Unit-Population and Medical Genomics Programme, Genomics Research Centre, Fondazione Human Technopole, Milan, Italy.
³² Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
³³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
³⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
³⁵ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
³⁶ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
³⁷ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
³⁸ Emerging Science and Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, UK.
³⁹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. shenx@fudan.edu.cn.
⁴⁰ Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China. shenx@fudan.edu.cn.
⁴¹ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK. shenx@fudan.edu.cn.
⁴² State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, China. shenx@fudan.edu.cn.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. shenx@fudan.edu.cn.

^# Contributed equally.

PMID: 39210026
DOI: 10.1038/s41562-024-01963-z

Meta-Analysis

The genetic landscape of neuro-related proteins in human plasma

Linda Repetto et al. Nat Hum Behav. 2024 Nov.

. 2024 Nov;8(11):2222-2234.

doi: 10.1038/s41562-024-01963-z. Epub 2024 Aug 29.

Authors

Affiliations

¹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
² Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
³ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁴ Health Data Science Centre, Fondazione Human Technopole, Milan, Italy.
⁵ State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, China.
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁸ MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia.
⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.
¹⁰ BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹¹ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹² Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
¹⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁷ Department of Epidemiology and Medical Statistics, Division of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
¹⁸ Institute of Biomedicine, Department of Laboratory Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁹ Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
²⁰ Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
²¹ Echinos Medical Centre, Echinos, Greece.
²² Anogia Medical Centre, Anogia, Greece.
²³ Lothian Birth Cohorts, University of Edinburgh, Edinburgh, UK.
²⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁵ Department of Clinical Genetics and Genomics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁶ Computational Medicine, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany.
²⁷ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
²⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center and Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁹ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece.
³⁰ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine and Health, Munich, Germany.
³¹ Biostatistics Unit-Population and Medical Genomics Programme, Genomics Research Centre, Fondazione Human Technopole, Milan, Italy.
³² Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
³³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
³⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
³⁵ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
³⁶ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
³⁷ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
³⁸ Emerging Science and Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, UK.
³⁹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. shenx@fudan.edu.cn.
⁴⁰ Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China. shenx@fudan.edu.cn.
⁴¹ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK. shenx@fudan.edu.cn.
⁴² State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, China. shenx@fudan.edu.cn.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. shenx@fudan.edu.cn.

^# Contributed equally.

PMID: 39210026
DOI: 10.1038/s41562-024-01963-z

Abstract

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioural traits and the disease aetiology of neuropsychiatric disorders. Here the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,000 individuals for 184 neuro-related proteins in human plasma. The analysis identified 125 cis-regulatory protein quantitative trait loci (cis-pQTL) and 164 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. At the cis-pQTL, multiple proteins shared a genetic basis with human behavioural traits such as alcohol and food intake, smoking and educational attainment, as well as neurological conditions and psychiatric disorders such as pain, neuroticism and schizophrenia. Integrating with established drug information, the causal inference analysis validated 52 out of 66 matched combinations of protein targets and diseases or side effects with available drugs while suggesting hundreds of repurposing and new therapeutic targets.

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Conflict of interest statement

Competing interests P.R.H.J.T. is a salaried employee of BioAge Labs, Inc. R.E.M. has received a speaker fee from Illumina, is an advisor to the Epigenetic Clock Development Foundation and is a scientific consultant for Optima Partners. E.W. is now an employee of AstraZeneca. Y.S.A. is now an employee of GSK. A.S.B. has received grants from AstraZeneca, Bayer, Biogen, BioMarin and Sanofi. A.M. is an employee of Pfizer. X.S. is the founder of Quantix BioSciences and has received a speaker fee from Olink Proteomics. The remaining authors declare no competing interests.

Update of

Genetic mechanisms of 184 neuro-related proteins in human plasma.
Repetto L, Chen J, Yang Z, Zhai R, Timmers PRHJ, Li T, Twait EL, May-Wilson S, Muckian MD, Prins BP, Png G, Kooperberg C, Johansson Å, Hillary RF, Wheeler E, Pan L, He Y, Klasson S, Ahmad S, Peters JE, Gilly A, Karaleftheri M, Tsafantakis E, Haessler J, Gyllensten U, Harris SE, Wareham NJ, Göteson A, Lagging C, Ikram MA, van Duijn CM, Jern C, Landén M, Langenberg C, Deary IJ, Marioni RE, Enroth S, Reiner AP, Dedoussis G, Zeggini E, Butterworth AS, Mälarstig A, Wilson JF, Navarro P, Shen X. Repetto L, et al. medRxiv [Preprint]. 2023 Feb 14:2023.02.10.23285650. doi: 10.1101/2023.02.10.23285650. medRxiv. 2023. Update in: Nat Hum Behav. 2024 Nov;8(11):2222-2234. doi: 10.1038/s41562-024-01963-z. PMID: 36824751 Free PMC article. Updated. Preprint.
Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.
Repetto L, Chen J, Yang Z, Zhai R, Timmers PRHJ, Li T, Twait EL, May-Wilson S, Muckian MD, Prins BP, Png G, Kooperberg C, Johansson Å, Hillary RF, Wheeler E, Pan L, He Y, Klasson S, Ahmad S, Peters JE, Gilly A, Karaleftheri M, Tsafantakis E, Haessler J, Gyllensten U, Harris SE, Wareham NJ, Göteson A, Lagging C, Ikram MA, van Duijn CM, Jern C, Landén M, Langenberg C, Deary IJ, Marioni RE, Enroth S, Reiner AP, Dedoussis G, Zeggini E, Butterworth AS, Mälarstig A, Wilson JF, Navarro P, Shen X. Repetto L, et al. Res Sq [Preprint]. 2023 Mar 31:rs.3.rs-2720355. doi: 10.21203/rs.3.rs-2720355/v1. Res Sq. 2023. Update in: Nat Hum Behav. 2024 Nov;8(11):2222-2234. doi: 10.1038/s41562-024-01963-z. PMID: 37034613 Free PMC article. Updated. Preprint.

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The genetic landscape of neuro-related proteins in human plasma

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The genetic landscape of neuro-related proteins in human plasma

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Abstract

Conflict of interest statement

Update of

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