[article]
| Titre : |
Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| Type de document : |
texte imprimé |
| Auteurs : |
Yuanxin ZHONG, Auteur ; Larry W. BAUM, Auteur ; Justin D. TUBBS, Auteur ; Rui YE, Auteur ; Lu Hua CHEN, Auteur ; Tian WU, Auteur ; Se-fong HUNG, Auteur ; Chun-pan TANG, Auteur ; Ting-pong HO, Auteur ; Robert MOYZIS, Auteur ; James SWANSON, Auteur ; Chi-chiu LEE, Auteur ; Pak C. SHAM, Auteur ; Patrick W.L. LEUNG, Auteur |
| Langues : |
Anglais (eng) |
| Mots-clés : |
Humans Attention Deficit Disorder with Hyperactivity/genetics/immunology/physiopathology Cerebellum/growth & development/diagnostic imaging/physiopathology Male Female Genome-Wide Association Study Genetic Predisposition to Disease Child Magnetic Resonance Imaging Hong Kong Polymorphism, Single Nucleotide Infant Adhd Cerebellum Common variant Immune response Late-infancy Low-frequency / rare variant University of Hong Kong-New Territories East Cluster, the Hospital Authority Kowloon Central and Kowloon West Cluster Clinical Research Ethics Committee provided ethical approval for this study, which complies with the most recent Declaration of Helsinki. All participants provided informed consent for the current study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for low-frequency / rare variants. METHODS: In this study, we aimed to investigate the contributions of both common and low-frequency / rare variants to ADHD in a Hong Kong sample. Our sample comprised 279 cases and 432 controls who underwent genotyping using the Illumina Infinium Global Screening Array. We employed various analytical methods at different levels, while also leveraging multi-omics data and large-scale summary statistics to comprehensively analyze the genetic basis of ADHD. RESULTS: We identified 41 potential genomic risk loci with a suggestive association (p < 1e(-4)), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. In low-frequency / rare variant analyses, we discovered the correlations between ADHD and collapsing effects of rare damaging variants in TEP1, MTMR10, DBH, TBCC, and ANO1. Based on biological and functional profiles of the potential risk genes and gene sets, both common and low-frequency / rare variant analyses demonstrated that ADHD genetic risk was associated with immune processes. CONCLUSIONS: These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective. The current study identified convergent risk factors from common and low-frequency / rare variants, which implicates vulnerability in late-infancy brain development, affecting especially the cerebellum, and the involvement of immune processes. |
| En ligne : |
https://dx.doi.org/10.1186/s11689-025-09626-4 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 |
in Journal of Neurodevelopmental Disorders > 17 (2025)
[article] Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD [texte imprimé] / Yuanxin ZHONG, Auteur ; Larry W. BAUM, Auteur ; Justin D. TUBBS, Auteur ; Rui YE, Auteur ; Lu Hua CHEN, Auteur ; Tian WU, Auteur ; Se-fong HUNG, Auteur ; Chun-pan TANG, Auteur ; Ting-pong HO, Auteur ; Robert MOYZIS, Auteur ; James SWANSON, Auteur ; Chi-chiu LEE, Auteur ; Pak C. SHAM, Auteur ; Patrick W.L. LEUNG, Auteur. Langues : Anglais ( eng) in Journal of Neurodevelopmental Disorders > 17 (2025)
| Mots-clés : |
Humans Attention Deficit Disorder with Hyperactivity/genetics/immunology/physiopathology Cerebellum/growth & development/diagnostic imaging/physiopathology Male Female Genome-Wide Association Study Genetic Predisposition to Disease Child Magnetic Resonance Imaging Hong Kong Polymorphism, Single Nucleotide Infant Adhd Cerebellum Common variant Immune response Late-infancy Low-frequency / rare variant University of Hong Kong-New Territories East Cluster, the Hospital Authority Kowloon Central and Kowloon West Cluster Clinical Research Ethics Committee provided ethical approval for this study, which complies with the most recent Declaration of Helsinki. All participants provided informed consent for the current study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for low-frequency / rare variants. METHODS: In this study, we aimed to investigate the contributions of both common and low-frequency / rare variants to ADHD in a Hong Kong sample. Our sample comprised 279 cases and 432 controls who underwent genotyping using the Illumina Infinium Global Screening Array. We employed various analytical methods at different levels, while also leveraging multi-omics data and large-scale summary statistics to comprehensively analyze the genetic basis of ADHD. RESULTS: We identified 41 potential genomic risk loci with a suggestive association (p < 1e(-4)), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. In low-frequency / rare variant analyses, we discovered the correlations between ADHD and collapsing effects of rare damaging variants in TEP1, MTMR10, DBH, TBCC, and ANO1. Based on biological and functional profiles of the potential risk genes and gene sets, both common and low-frequency / rare variant analyses demonstrated that ADHD genetic risk was associated with immune processes. CONCLUSIONS: These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective. The current study identified convergent risk factors from common and low-frequency / rare variants, which implicates vulnerability in late-infancy brain development, affecting especially the cerebellum, and the involvement of immune processes. |
| En ligne : |
https://dx.doi.org/10.1186/s11689-025-09626-4 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 |
|  |
Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD in Journal of Neurodevelopmental Disorders, 17 (2025)
