Systematic Review and Meta-Analysis: Phenotypic Correlates of the Autism Polygenic Score

Melanie M de Wit; Morgan J Morgan; Ilan Libedinsky; Chloe Austerberry; Sander Begeer; Abdel Abdellaoui; Angelica Ronald; Tinca J C Polderman

doi:10.1016/j.jaacop.2025.04.001

Systematic Review and Meta-Analysis: Phenotypic Correlates of the Autism Polygenic Score

Melanie M de Wit, Morgan J Morgan, Ilan Libedinsky, Chloe Austerberry, Sander Begeer, Abdel Abdellaoui, Angelica Ronald, Tinca J C Polderman

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

OBJECTIVE: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The primary objective of this study was to clarify the associations between the autism polygenic score and autism diagnosis, autistic traits, and related behavioral and neurobiological traits.

METHOD: Peer-reviewed studies written in English reporting univariate associations were included. PubMed, Web of Science, PsycINFO, and Scopus were systematically searched on November 2, 2022, and January 6, 2023. The quality of included studies was assessed using the QUIPS tool, systematic review with best-evidence synthesis was applied, and meta-analyses were performed if >5 studies were conducted on similar phenotypes.

RESULTS: Of 72 eligible studies (pooled N = 720,087), 61 received high-quality ratings. Meta-analysis of 9 studies revealed strong evidence for an association between the autism polygenic score and autism diagnosis (meta-analytic r = 0.158 [95% CI 0.067-0.249]). The systematic review revealed strong evidence for an association with social behavior, depression, and motor skills and weak evidence for physical activity. Associations with other outcomes were inconclusive, and effect sizes were generally small (median r = 0.03).

CONCLUSION: The autism polygenic score is consistently associated with autism diagnosis and a small number of co-occurring traits. Associations with many other traits and conditions are not significant. Due to its inconsistent associations and limited generalizability, it must be emphasized that the autism polygenic score does not have clinical utility and should be applied only for scientific purposes, with improvements needed for a deeper understanding of the polygenic underpinnings of autism.

DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

STUDY REGISTRATION INFORMATION: The Association Between Polygenic Scores for Autism Spectrum Disorder and Autism Spectrum Disorder and Associated Traits: A Systematic Review and Meta-analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42022307993.

Original language	English
Pages (from-to)	839-851
Number of pages	13
Journal	JAACAP Open
Volume	3
Issue number	4
Early online date	14 Apr 2025
DOIs	https://doi.org/10.1016/j.jaacop.2025.04.001
Publication status	Published - Dec 2025

Bibliographical note

Funding

Disclosure: Melanie M. de Wit has received additional funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Nationale WetenschapsAgenda ( NWA ) grant number NWA.1397.24.008. Tinca J.C. Polderman and Sander Begeer have received additional funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Nationale WetenschapsAgenda (NWA) grant number NWA.1518.22.136 SCANNER. Angelica Ronald received funding from the Simons Foundation Autism Research Initiative (grant 724306) and receives an honorarium for her role as an editor of Journal of Child Psychology and Psychiatry. Morgan J. Morgan, Ilan Libedinsky, Chloe Austerberry, and Abdel Abdellaoui have reported no biomedical financial interests or potential conflicts of interest. Disclosure: Melanie M. de Wit has received additional funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Nationale WetenschapsAgenda (NWA) grant number NWA.1397.24.008. Tinca J.C. Polderman and Sander Begeer have received additional funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Nationale WetenschapsAgenda (NWA) grant number NWA.1518.22.136 SCANNER. Angelica Ronald received funding from the Simons Foundation Autism Research Initiative (grant 724306) and receives an honorarium for her role as an editor of Journal of Child Psychology and Psychiatry. Morgan J. Morgan, Ilan Libedinsky, Chloe Austerberry, and Abdel Abdellaoui have reported no biomedical financial interests or potential conflicts of interest. This work was supported by ZonMw grant number 60-63600-98-834 (de Wit, Begeer, Polderman) and the Amsterdam UMC Fellowship (Abdellaoui). This work was supported by ZonMw grant number 60-63600-98-834 (de Wit, Begeer, Polderman) and the Amsterdam UMC Fellowship (Abdellaoui).

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Nationale Wetenschapsagenda
Simons Foundation Autism Research Initiative	724306
ZonMw	60-63600-98-834
Exacte en Natuurwetenschappen	NWA.1397.24.008, NWA.1518.22.136 SCANNER

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@article{f25a610b38274e8c9d84283db9091351,

title = "Systematic Review and Meta-Analysis: Phenotypic Correlates of the Autism Polygenic Score",

abstract = "OBJECTIVE: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The primary objective of this study was to clarify the associations between the autism polygenic score and autism diagnosis, autistic traits, and related behavioral and neurobiological traits.METHOD: Peer-reviewed studies written in English reporting univariate associations were included. PubMed, Web of Science, PsycINFO, and Scopus were systematically searched on November 2, 2022, and January 6, 2023. The quality of included studies was assessed using the QUIPS tool, systematic review with best-evidence synthesis was applied, and meta-analyses were performed if >5 studies were conducted on similar phenotypes.RESULTS: Of 72 eligible studies (pooled N = 720,087), 61 received high-quality ratings. Meta-analysis of 9 studies revealed strong evidence for an association between the autism polygenic score and autism diagnosis (meta-analytic r = 0.158 [95\% CI 0.067-0.249]). The systematic review revealed strong evidence for an association with social behavior, depression, and motor skills and weak evidence for physical activity. Associations with other outcomes were inconclusive, and effect sizes were generally small (median r = 0.03). CONCLUSION: The autism polygenic score is consistently associated with autism diagnosis and a small number of co-occurring traits. Associations with many other traits and conditions are not significant. Due to its inconsistent associations and limited generalizability, it must be emphasized that the autism polygenic score does not have clinical utility and should be applied only for scientific purposes, with improvements needed for a deeper understanding of the polygenic underpinnings of autism.DIVERSITY \& INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.STUDY REGISTRATION INFORMATION: The Association Between Polygenic Scores for Autism Spectrum Disorder and Autism Spectrum Disorder and Associated Traits: A Systematic Review and Meta-analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42022307993.",

author = "\{de Wit\}, \{Melanie M\} and Morgan, \{Morgan J\} and Ilan Libedinsky and Chloe Austerberry and Sander Begeer and Abdel Abdellaoui and Angelica Ronald and Polderman, \{Tinca J C\}",

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doi = "10.1016/j.jaacop.2025.04.001",

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T1 - Systematic Review and Meta-Analysis

T2 - Phenotypic Correlates of the Autism Polygenic Score

AU - de Wit, Melanie M

AU - Morgan, Morgan J

AU - Libedinsky, Ilan

AU - Austerberry, Chloe

AU - Begeer, Sander

AU - Abdellaoui, Abdel

AU - Ronald, Angelica

AU - Polderman, Tinca J C

PY - 2025/12

Y1 - 2025/12

N2 - OBJECTIVE: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The primary objective of this study was to clarify the associations between the autism polygenic score and autism diagnosis, autistic traits, and related behavioral and neurobiological traits.METHOD: Peer-reviewed studies written in English reporting univariate associations were included. PubMed, Web of Science, PsycINFO, and Scopus were systematically searched on November 2, 2022, and January 6, 2023. The quality of included studies was assessed using the QUIPS tool, systematic review with best-evidence synthesis was applied, and meta-analyses were performed if >5 studies were conducted on similar phenotypes.RESULTS: Of 72 eligible studies (pooled N = 720,087), 61 received high-quality ratings. Meta-analysis of 9 studies revealed strong evidence for an association between the autism polygenic score and autism diagnosis (meta-analytic r = 0.158 [95% CI 0.067-0.249]). The systematic review revealed strong evidence for an association with social behavior, depression, and motor skills and weak evidence for physical activity. Associations with other outcomes were inconclusive, and effect sizes were generally small (median r = 0.03). CONCLUSION: The autism polygenic score is consistently associated with autism diagnosis and a small number of co-occurring traits. Associations with many other traits and conditions are not significant. Due to its inconsistent associations and limited generalizability, it must be emphasized that the autism polygenic score does not have clinical utility and should be applied only for scientific purposes, with improvements needed for a deeper understanding of the polygenic underpinnings of autism.DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.STUDY REGISTRATION INFORMATION: The Association Between Polygenic Scores for Autism Spectrum Disorder and Autism Spectrum Disorder and Associated Traits: A Systematic Review and Meta-analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42022307993.

AB - OBJECTIVE: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The primary objective of this study was to clarify the associations between the autism polygenic score and autism diagnosis, autistic traits, and related behavioral and neurobiological traits.METHOD: Peer-reviewed studies written in English reporting univariate associations were included. PubMed, Web of Science, PsycINFO, and Scopus were systematically searched on November 2, 2022, and January 6, 2023. The quality of included studies was assessed using the QUIPS tool, systematic review with best-evidence synthesis was applied, and meta-analyses were performed if >5 studies were conducted on similar phenotypes.RESULTS: Of 72 eligible studies (pooled N = 720,087), 61 received high-quality ratings. Meta-analysis of 9 studies revealed strong evidence for an association between the autism polygenic score and autism diagnosis (meta-analytic r = 0.158 [95% CI 0.067-0.249]). The systematic review revealed strong evidence for an association with social behavior, depression, and motor skills and weak evidence for physical activity. Associations with other outcomes were inconclusive, and effect sizes were generally small (median r = 0.03). CONCLUSION: The autism polygenic score is consistently associated with autism diagnosis and a small number of co-occurring traits. Associations with many other traits and conditions are not significant. Due to its inconsistent associations and limited generalizability, it must be emphasized that the autism polygenic score does not have clinical utility and should be applied only for scientific purposes, with improvements needed for a deeper understanding of the polygenic underpinnings of autism.DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.STUDY REGISTRATION INFORMATION: The Association Between Polygenic Scores for Autism Spectrum Disorder and Autism Spectrum Disorder and Associated Traits: A Systematic Review and Meta-analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42022307993.

U2 - 10.1016/j.jaacop.2025.04.001

DO - 10.1016/j.jaacop.2025.04.001

M3 - Article

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SN - 2949-7329

VL - 3

SP - 839

EP - 851

JO - JAACAP Open

JF - JAACAP Open

IS - 4

ER -

Systematic Review and Meta-Analysis: Phenotypic Correlates of the Autism Polygenic Score

Abstract

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