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| PMID |
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| TITLE |
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| Empirical evaluation of analytic validity of polygenic scores. |
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| ABSTRACT |
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| BACKGROUND: Polygenic scores (PGSs) are weighted sum scores of trait-associated alleles from up to millions of SNPs. As PGS research pivots to translation into health care settings a key issue for laboratories providing PGS is demonstration of analytical validity of PGS. METHODS: We report data from 6 individuals who have been genotyped multiple times using the same and different technologies. These data were generated as part of standard experimental design for quality control purposes in two research settings over many studies and over many years. Using this opportunistic design of technical variability, we provide an empirical evaluation of technical reproducibility of PGS from 115 traits of different genetic architectures. RESULTS: Given a predefined set of SNP weights variability in PGS can reflect only SNP missingness or incorrect genotype call. We find very high reproducibility of SNP genotypes. In particular, the technical reproducibility of PGS generated from the same array technology and processed through the same quality control and imputation pipeline is very high. However, impact of missing SNPs varies between traits depending on the SNP’s weight for a trait. We provide a PGS quality score statistic (PGS:QS) that can be reported for each trait-specific score for an individual, to provide a quantitative assessment of the proportion of variation of the score that is captured by the SNPs genotyped/imputed for the individual. We provide an algorithm (PGS-impute) that updates the SNP weights of the scoring algorithm to the SNPs available for an individual, improving PGS accuracy. CONCLUSIONS: While validity of directly measured genotypes (whether from microarray or whole genome sequencing) is well-established, objective approaches to evaluate analytical reproducibility of PGS post-genotyping pipeline have been lacking. Here, we provide empirical data and an analysis framework which can be used by PGS providers to support understanding of analytical reproducibility and robustness. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2025/09/15 |
| accepted |
2026/04/07 |
| medline |
2026/06/28 06:34 |
| pubmed |
2026/04/24 00:32 |
| entrez |
2026/04/23 23:57 |
| pmc-release |
2026/04/23 |
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| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Lin T |
|
Lin |
Tian |
T |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Zeng J |
|
Zeng |
Jian |
J |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Wallace L |
|
Wallace |
Leanne |
L |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Ziser L |
|
Ziser |
Laura |
L |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Shah S |
|
Shah |
Sonia |
S |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Pain O |
|
Pain |
Oliver |
O |
|
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. |
| Nolte IM |
|
Nolte |
Ilja M |
IM |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. |
| Snieder H |
|
Snieder |
Harold |
H |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. |
|
Lifelines Cohort Study |
|
|
|
|
|
| James PA |
|
James |
Paul A |
PA |
|
Peter MacCallum Cancer Centre, Melbourne, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Visscher PM |
|
Visscher |
Peter M |
PM |
|
Nuffield Department of Population Health, University of Oxford, Oxford, UK. |
| Lee E |
|
Lee |
Eric |
E |
|
Preciselee, Sydney, NSW, 2065, Australia. |
| Yengo L |
|
Yengo |
Loic |
L |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Henders AK |
|
Henders |
Anjali K |
AK |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
Department of Psychiatry, University of Oxford, Oxford, UK. Naomi.wray@psych.ox.ac.uk. |
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| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Aguirre-Gamboa |
Raul |
R |
|
| Deelen |
Patrick |
P |
|
| Franke |
Lude |
L |
|
| Kuivenhoven |
Jan A |
JA |
|
| Lopera Maya |
Esteban A |
EA |
|
| Sanna |
Serena |
S |
|
| Swertz |
Morris A |
MA |
|
| Vonk |
Judith M |
JM |
|
| Wijmenga |
Cisca |
C |
|
|
| JOURNAL |
|
| VOLUME: 18 |
| ISSUE: 1 |
| TITLE: Genome medicine |
| ISOABBREVIATION: Genome Med |
| YEAR: 2026 |
| MONTH: Apr |
| DAY: 23 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1756-994X |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Genome Med |
| COUNTRY: England |
| ISSNLINKING: 1756-994X |
| NLMUNIQUEID: 101475844 |
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| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| 1177268 |
National Health and Medical Research Council |
|
| 2000001 |
National Health and Medical Research Council |
|
| 1134300 |
National Health and Medical Research Council |
|
| 1173790 |
National Health and Medical Research Council |
|
| 222811/Z/21/Z |
Wellcome Trust fellowship |
|
| FL180100072 |
Australian Research Council |
|
| 1R01MH121545-01:5115417 |
NIMH NIH HHS |
United States |
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| GENERAL NOTE |
|
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| KEYWORDS |
|
| KEYWORD |
| Polygenic risk |
| Polygenic scores |
| Reproducibility |
| Technical replication |
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| MESH HEADINGS |
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| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
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| Polymorphism, Single Nucleotide |
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| Multifactorial Inheritance |
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| Reproducibility of Results |
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| Genetic Risk Score |
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| Genotype |
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| Genome-Wide Association Study |
|
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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