Enhancing the discriminatory power of polygenic scores for ADHD and autism in clinical and non-clinical samples / James J. LI in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Enhancing the discriminatory power of polygenic scores for ADHD and autism in clinical and non-clinical samples Type de document : texte imprimé Auteurs : James J. LI, Auteur ; Quanfa HE, Auteur ; Stephen DORN, Auteur ; Zihang WANG, Auteur ; Qiongshi LU, Auteur Langues : Anglais (eng) Mots-clés : Humans  Attention Deficit Disorder with Hyperactivity/genetics/diagnosis/epidemiology  Multifactorial Inheritance/genetics  Autism Spectrum Disorder/genetics/diagnosis/epidemiology  Male  Female  Child  Adolescent  Cohort Studies  Autistic Disorder/genetics  Adhd  Asd  GenomicSEM  Neurodevelopment  Polygenic scores  Neurodevelopmental Cohort (PNC) and the Simons Foundation Powering Autism  Research for Knowledge (SPARK) datasets are both publicly available,  de-identified datasets. This study was exempt from requiring approval from the  University of Wisconsin-Madison Health Sciences Institutional Review Board (see  "Category 4" exemption: https://kb.wisc.edu/gsadminkb/page.php?id=29465 ).  Consent for publication: Not applicable. Competing interests: The authors declare  no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their predictive power for focal outcomes. However, they lack discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD). METHODS: Genomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples - the Philadelphia Neurodevelopmental Cohort (N = 4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N = 5,045) cohort. RESULTS: PGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes. CONCLUSIONS: Psychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications. En ligne : https://dx.doi.org/10.1186/s11689-025-09620-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Enhancing the discriminatory power of polygenic scores for ADHD and autism in clinical and non-clinical samples [texte imprimé] / James J. LI, Auteur ; Quanfa HE, Auteur ; Stephen DORN, Auteur ; Zihang WANG, Auteur ; Qiongshi LU, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Humans  Attention Deficit Disorder with Hyperactivity/genetics/diagnosis/epidemiology  Multifactorial Inheritance/genetics  Autism Spectrum Disorder/genetics/diagnosis/epidemiology  Male  Female  Child  Adolescent  Cohort Studies  Autistic Disorder/genetics  Adhd  Asd  GenomicSEM  Neurodevelopment  Polygenic scores  Neurodevelopmental Cohort (PNC) and the Simons Foundation Powering Autism  Research for Knowledge (SPARK) datasets are both publicly available,  de-identified datasets. This study was exempt from requiring approval from the  University of Wisconsin-Madison Health Sciences Institutional Review Board (see  "Category 4" exemption: https://kb.wisc.edu/gsadminkb/page.php?id=29465 ).  Consent for publication: Not applicable. Competing interests: The authors declare  no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their predictive power for focal outcomes. However, they lack discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD). METHODS: Genomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples - the Philadelphia Neurodevelopmental Cohort (N = 4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N = 5,045) cohort. RESULTS: PGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes. CONCLUSIONS: Psychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications. En ligne : https://dx.doi.org/10.1186/s11689-025-09620-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort / Quanfa HE in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort Type de document : texte imprimé Auteurs : Quanfa HE, Auteur ; Taylor J. KEDING, Auteur ; Qi ZHANG, Auteur ; Jiacheng MIAO, Auteur ; Justin D. RUSSELL, Auteur ; Ryan J. HERRINGA, Auteur ; Qiongshi LU, Auteur ; Brittany G. TRAVERS, Auteur ; James J. LI, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Humans  Attention Deficit Disorder with Hyperactivity/genetics  Neurosciences  Brain/diagnostic imaging  Cerebral Cortex  Gray Matter/diagnostic imaging  Adhd  Brain volume  Functional annotation  Multiple mediation  Polygenic scores Index. décimale : PER Périodiques Résumé : BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures. En ligne : https://dx.doi.org/10.1186/s11689-023-09498-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort [texte imprimé] / Quanfa HE, Auteur ; Taylor J. KEDING, Auteur ; Qi ZHANG, Auteur ; Jiacheng MIAO, Auteur ; Justin D. RUSSELL, Auteur ; Ryan J. HERRINGA, Auteur ; Qiongshi LU, Auteur ; Brittany G. TRAVERS, Auteur ; James J. LI, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Adolescent  Humans  Attention Deficit Disorder with Hyperactivity/genetics  Neurosciences  Brain/diagnostic imaging  Cerebral Cortex  Gray Matter/diagnostic imaging  Adhd  Brain volume  Functional annotation  Multiple mediation  Polygenic scores Index. décimale : PER Périodiques Résumé : BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures. En ligne : https://dx.doi.org/10.1186/s11689-023-09498-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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