---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '21488'
abstract:
- lang: eng
  text: Human height is a model for the genetic analysis of complex traits, and recent
    studies suggest the presence of thousands of common genetic variant associations
    and hundreds of low-frequency/rare variants. Here, we develop a new algorithmic
    paradigm based on approximate message passing (genomic vector approximate message
    passing [gVAMP]) for identifying DNA sequence variants associated with complex
    traits and common diseases in large-scale whole-genome sequencing (WGS) data.
    We show that gVAMP accurately localizes associations to variants with the correct
    frequency and position in the DNA, outperforming existing fine-mapping methods
    in selecting the appropriate genetic variants within WGS data. We then apply gVAMP
    to jointly model the relationship of tens of millions of WGS variants with human
    height in hundreds of thousands of UK Biobank individuals. We identify 59 rare
    variants and gene burden scores alongside many hundreds of DNA regions containing
    common variant associations and show that understanding the genetic basis of complex
    traits will require the joint analysis of hundreds of millions of variables measured
    on millions of people. The polygenic risk scores obtained from gVAMP have high
    accuracy (including a prediction accuracy of ∼46% for human height) and outperform
    current methods for downstream tasks such as mixed linear model association testing
    across 13 UK Biobank traits. In conclusion, gVAMP offers a scalable foundation
    for a wider range of analyses in WGS data.
acknowledgement: We thank Malgorzata Borczyk for creating the gene burden scores.
  We thank Robin Beaumont, Amedeo Roberto Esposito, Gareth Hawkes, Philip Schniter,
  Matthew Stephens, Pragya Sur, Peter Visscher, Michael Weedon, and Harry Wright for
  providing valuable suggestions and comments on earlier versions of the work. This
  project was funded by a Lopez-Loreta Prize to M.M., an SNSF Eccellenza Grant to
  M.R.R. (PCEGP3-181181), an ERC Starting Grant to M.M. (INF2, project number 101161364),
  and core funding from ISTA. High-performance computing was supported by the Scientific
  Service Units (SSU) of ISTA through resources provided by Scientific Computing (SciComp).
  We would like to acknowledge the participants and investigators of the UK Biobank
  study. We gratefully acknowledge the All of Us participants for their contributions,
  without whom this research would not have been possible. We also thank the National
  Institutes of Health All of Us Research Program for making available the participant
  data (and/or samples and/or cohort) examined in this study.
article_number: '101162'
article_processing_charge: Yes
article_type: original
author:
- first_name: Al
  full_name: Depope, Al
  id: 0b77531d-dbcd-11ea-9d1d-a8eee0bf3830
  last_name: Depope
- first_name: Jakub
  full_name: Bajzik, Jakub
  id: b995e25b-8c4b-11ed-a6d8-f71b7bcd6122
  last_name: Bajzik
- first_name: Marco
  full_name: Mondelli, Marco
  id: 27EB676C-8706-11E9-9510-7717E6697425
  last_name: Mondelli
  orcid: 0000-0002-3242-7020
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
citation:
  ama: Depope A, Bajzik J, Mondelli M, Robinson MR. Joint modeling of whole-genome
    sequencing data for human height via approximate message passing. <i>Cell Genomics</i>.
    2026. doi:<a href="https://doi.org/10.1016/j.xgen.2026.101162">10.1016/j.xgen.2026.101162</a>
  apa: Depope, A., Bajzik, J., Mondelli, M., &#38; Robinson, M. R. (2026). Joint modeling
    of whole-genome sequencing data for human height via approximate message passing.
    <i>Cell Genomics</i>. Elsevier. <a href="https://doi.org/10.1016/j.xgen.2026.101162">https://doi.org/10.1016/j.xgen.2026.101162</a>
  chicago: Depope, Al, Jakub Bajzik, Marco Mondelli, and Matthew Richard Robinson.
    “Joint Modeling of Whole-Genome Sequencing Data for Human Height via Approximate
    Message Passing.” <i>Cell Genomics</i>. Elsevier, 2026. <a href="https://doi.org/10.1016/j.xgen.2026.101162">https://doi.org/10.1016/j.xgen.2026.101162</a>.
  ieee: A. Depope, J. Bajzik, M. Mondelli, and M. R. Robinson, “Joint modeling of
    whole-genome sequencing data for human height via approximate message passing,”
    <i>Cell Genomics</i>. Elsevier, 2026.
  ista: Depope A, Bajzik J, Mondelli M, Robinson MR. 2026. Joint modeling of whole-genome
    sequencing data for human height via approximate message passing. Cell Genomics.,
    101162.
  mla: Depope, Al, et al. “Joint Modeling of Whole-Genome Sequencing Data for Human
    Height via Approximate Message Passing.” <i>Cell Genomics</i>, 101162, Elsevier,
    2026, doi:<a href="https://doi.org/10.1016/j.xgen.2026.101162">10.1016/j.xgen.2026.101162</a>.
  short: A. Depope, J. Bajzik, M. Mondelli, M.R. Robinson, Cell Genomics (2026).
corr_author: '1'
date_created: 2026-03-23T15:10:03Z
date_published: 2026-02-18T00:00:00Z
date_updated: 2026-07-23T05:33:49Z
day: '18'
ddc:
- '000'
- '570'
department:
- _id: MaMo
- _id: MaRo
doi: 10.1016/j.xgen.2026.101162
has_accepted_license: '1'
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1016/j.xgen.2026.101162
month: '02'
oa: 1
oa_version: Published Version
project:
- _id: 059876FA-7A3F-11EA-A408-12923DDC885E
  name: Prix Lopez-Loretta 2019 - Marco Mondelli
- _id: 911e6d1f-16d5-11f0-9cad-c5c68c6a1cdf
  grant_number: '101161364'
  name: 'Inference in High Dimensions: Light-speed Algorithms and Information Limits'
- _id: 9B8D11D6-BA93-11EA-9121-9846C619BF3A
  grant_number: PCEGP3_181181
  name: Improving estimation and prediction of common complex disease risk
publication: Cell Genomics
publication_identifier:
  eissn:
  - 2666-979X
publication_status: epub_ahead
publisher: Elsevier
quality_controlled: '1'
related_material:
  link:
  - description: News on ISTA website
    relation: press_release
    url: https://ista.ac.at/en/news/big-data-and-human-height/
  record:
  - id: '22258'
    relation: dissertation_contains
    status: public
status: public
title: Joint modeling of whole-genome sequencing data for human height via approximate
  message passing
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: ba8df636-2132-11f1-aed0-ed93e2281fdd
year: '2026'
...
---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '20816'
abstract:
- lang: eng
  text: "Background: DNA methylation (DNAm) can regulate gene expression, and its
    genome-wide patterns (epigenetic scores or EpiScores) can act as biomarkers for
    complex traits. The relative stability of methylation profiles may enable better
    assessment of chronic exposures compared to single time-point protein measures.
    We present the first large-scale epigenetic study of the highly-abundant serum
    proteome measured via ultra-high throughput mass spectrometry in 14,671 samples
    from the Generation Scotland cohort. We further demonstrate the first large-scale
    comparison of protein EpiScores and their respective proteins as predictors of
    incident cardiovascular disease.\r\n\r\nResults: Marginal epigenome-wide association
    models, adjusting for age, sex, measurement batch, estimated white cell proportions,
    BMI, smoking and methylation principal components, reveal 15,855 significant CpG
    – protein associations across 125 of 133 proteins PBonferroni < 2.71 × 10-10.
    Bayesian epigenome-wide association studies of the same 133 proteins reveal 697
    CpG-Protein associations (posterior inclusion probability > 0.95). 112 protein
    EpiScores correlate significantly with their respective protein in a holdout test-set.
    Of these, sixteen associate significantly with incident all-cause cardiovascular
    disease (Nevents=191) compared to one measured protein.\r\n\r\nConclusions: We
    highlight a complex interplay between the blood-based methylome and proteome.
    Importantly, we show that protein EpiScores correlate with measured proteins and
    demonstrate that the, as-yet understudied, high-abundance proteome may yield clinically
    relevant biomarkers. The protein EpiScores demonstrate more significant associations
    with cardiovascular disease than directly measured proteins, suggesting their
    potential as clinical biomarkers for monitoring or predicting disease risk. We
    suggest that biomarker development could be enhanced by the consideration of protein
    EpiScores alongside measured proteins."
acknowledgement: "Generation Scotland received core support from the Chief Scientist
  Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish
  Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z].
  Genotyping of the Generation Scotland samples was carried out by the Genetics Core
  Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh,
  Scotland and was funded by the Medical Research Council UK and the Wellcome Trust
  (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally”
  (STRADL) Reference 104036/Z/14/Z). The DNA methylation profiling and analysis was
  supported by Wellcome Investigator Award 220857/Z/20/Z and Grant 104036/Z/14/Z (PI:
  Prof AM McIntosh) and through funding from NARSAD (Ref: 27404; awardee: Dr DM Howard)
  and the Royal College of Physicians of Edinburgh (Sim Fellowship; Awardee: Prof
  HC Whalley).\r\nJAR is a University of Edinburgh Clinical Academic Track PhD student,
  supported by the Wellcome Trust (319878/Z/24/Z). ADC was supported by a Medical
  Research Council PhD Studentship in Precision Medicine with funding from the Medical
  Research Council Doctoral Training Program and the University of Edinburgh College
  of Medicine and Veterinary Medicine. HMS is a student on the University of Edinburgh
  Translational Neuroscience PhD programme funded by the Wellcome Trust (218493/Z/19/Z).
  CH was funded by MRC Human Genetics Unit program (QTL in Health and Disease) (grant
  U.MC_UU_00007/10). S.R.C. is supported by a Sir Henry Dale Fellowship jointly funded
  by the Wellcome Trust and the Royal Society (221890/Z/20/Z). JM and REM were supported
  by Alzheimer’s Society project grant AS-PG-19b-010."
article_number: '417'
article_processing_charge: Yes
article_type: original
author:
- first_name: Josephine A.
  full_name: Robertson, Josephine A.
  last_name: Robertson
- first_name: Jakub
  full_name: Bajzik, Jakub
  id: b995e25b-8c4b-11ed-a6d8-f71b7bcd6122
  last_name: Bajzik
- first_name: Spyros
  full_name: Vernardis, Spyros
  last_name: Vernardis
- first_name: Aleksandra D.
  full_name: Chybowska, Aleksandra D.
  last_name: Chybowska
- first_name: Daniel L.
  full_name: Mccartney, Daniel L.
  last_name: Mccartney
- first_name: Arturas
  full_name: Grauslys, Arturas
  last_name: Grauslys
- first_name: Jure
  full_name: Mur, Jure
  last_name: Mur
- first_name: Hannah M.
  full_name: Smith, Hannah M.
  last_name: Smith
- first_name: Archie
  full_name: Campbell, Archie
  last_name: Campbell
- first_name: Camilla
  full_name: Drake, Camilla
  last_name: Drake
- first_name: Hannah
  full_name: Grant, Hannah
  last_name: Grant
- first_name: Jamie
  full_name: Pearce, Jamie
  last_name: Pearce
- first_name: Tom C.
  full_name: Russ, Tom C.
  last_name: Russ
- first_name: Poppy
  full_name: Adkin, Poppy
  last_name: Adkin
- first_name: Matthew
  full_name: White, Matthew
  last_name: White
- first_name: Charles
  full_name: Brigden, Charles
  last_name: Brigden
- first_name: Christoph B.
  full_name: Messner, Christoph B.
  last_name: Messner
- first_name: David J.
  full_name: Porteous, David J.
  last_name: Porteous
- first_name: Caroline
  full_name: Hayward, Caroline
  last_name: Hayward
- first_name: Simon R.
  full_name: Cox, Simon R.
  last_name: Cox
- first_name: Aleksej
  full_name: Zelezniak, Aleksej
  last_name: Zelezniak
- first_name: Markus
  full_name: Ralser, Markus
  last_name: Ralser
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Riccardo E.
  full_name: Marioni, Riccardo E.
  last_name: Marioni
citation:
  ama: Robertson JA, Bajzik J, Vernardis S, et al. Methylome-wide association studies
    and epigenetic biomarker development for 133 mass spectrometry-assessed circulating
    proteins in 14,671 Generation Scotland participants. <i>Genome Biology</i>. 2025;26.
    doi:<a href="https://doi.org/10.1186/s13059-025-03892-0">10.1186/s13059-025-03892-0</a>
  apa: Robertson, J. A., Bajzik, J., Vernardis, S., Chybowska, A. D., Mccartney, D.
    L., Grauslys, A., … Marioni, R. E. (2025). Methylome-wide association studies
    and epigenetic biomarker development for 133 mass spectrometry-assessed circulating
    proteins in 14,671 Generation Scotland participants. <i>Genome Biology</i>. Springer
    Nature. <a href="https://doi.org/10.1186/s13059-025-03892-0">https://doi.org/10.1186/s13059-025-03892-0</a>
  chicago: Robertson, Josephine A., Jakub Bajzik, Spyros Vernardis, Aleksandra D.
    Chybowska, Daniel L. Mccartney, Arturas Grauslys, Jure Mur, et al. “Methylome-Wide
    Association Studies and Epigenetic Biomarker Development for 133 Mass Spectrometry-Assessed
    Circulating Proteins in 14,671 Generation Scotland Participants.” <i>Genome Biology</i>.
    Springer Nature, 2025. <a href="https://doi.org/10.1186/s13059-025-03892-0">https://doi.org/10.1186/s13059-025-03892-0</a>.
  ieee: J. A. Robertson <i>et al.</i>, “Methylome-wide association studies and epigenetic
    biomarker development for 133 mass spectrometry-assessed circulating proteins
    in 14,671 Generation Scotland participants,” <i>Genome Biology</i>, vol. 26. Springer
    Nature, 2025.
  ista: Robertson JA, Bajzik J, Vernardis S, Chybowska AD, Mccartney DL, Grauslys
    A, Mur J, Smith HM, Campbell A, Drake C, Grant H, Pearce J, Russ TC, Adkin P,
    White M, Brigden C, Messner CB, Porteous DJ, Hayward C, Cox SR, Zelezniak A, Ralser
    M, Robinson MR, Marioni RE. 2025. Methylome-wide association studies and epigenetic
    biomarker development for 133 mass spectrometry-assessed circulating proteins
    in 14,671 Generation Scotland participants. Genome Biology. 26, 417.
  mla: Robertson, Josephine A., et al. “Methylome-Wide Association Studies and Epigenetic
    Biomarker Development for 133 Mass Spectrometry-Assessed Circulating Proteins
    in 14,671 Generation Scotland Participants.” <i>Genome Biology</i>, vol. 26, 417,
    Springer Nature, 2025, doi:<a href="https://doi.org/10.1186/s13059-025-03892-0">10.1186/s13059-025-03892-0</a>.
  short: J.A. Robertson, J. Bajzik, S. Vernardis, A.D. Chybowska, D.L. Mccartney,
    A. Grauslys, J. Mur, H.M. Smith, A. Campbell, C. Drake, H. Grant, J. Pearce, T.C.
    Russ, P. Adkin, M. White, C. Brigden, C.B. Messner, D.J. Porteous, C. Hayward,
    S.R. Cox, A. Zelezniak, M. Ralser, M.R. Robinson, R.E. Marioni, Genome Biology
    26 (2025).
date_created: 2025-12-14T23:02:04Z
date_published: 2025-12-08T00:00:00Z
date_updated: 2025-12-15T13:19:41Z
day: '08'
ddc:
- '570'
department:
- _id: MaRo
doi: 10.1186/s13059-025-03892-0
external_id:
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  - '41361833'
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  file_size: 2206991
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intvolume: '        26'
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license: https://creativecommons.org/licenses/by/4.0/
month: '12'
oa: 1
oa_version: Published Version
pmid: 1
publication: Genome Biology
publication_identifier:
  eissn:
  - 1474-760X
  issn:
  - 1474-7596
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Methylome-wide association studies and epigenetic biomarker development for
  133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland
  participants
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
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...