Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD
Abstract 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, g...
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BMC
2025-06-01
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| Series: | Journal of Neurodevelopmental Disorders |
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| Online Access: | https://doi.org/10.1186/s11689-025-09626-4 |
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| author | Yuanxin Zhong Larry W. Baum Justin D. Tubbs Rui Ye Lu Hua Chen Tian Wu Se-Fong Hung Chun-Pan Tang Ting-Pong Ho Robert Moyzis James Swanson Chi-Chiu Lee Pak C. Sham Patrick W. L. Leung |
| author_facet | Yuanxin Zhong Larry W. Baum Justin D. Tubbs Rui Ye Lu Hua Chen Tian Wu Se-Fong Hung Chun-Pan Tang Ting-Pong Ho Robert Moyzis James Swanson Chi-Chiu Lee Pak C. Sham Patrick W. L. Leung |
| author_sort | Yuanxin Zhong |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-c40fcba7b3704ce1a3fee99d95c26a1f |
| institution | OA Journals |
| issn | 1866-1955 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Journal of Neurodevelopmental Disorders |
| spelling | doaj-art-c40fcba7b3704ce1a3fee99d95c26a1f2025-08-20T02:10:29ZengBMCJournal of Neurodevelopmental Disorders1866-19552025-06-0117111410.1186/s11689-025-09626-4Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHDYuanxin Zhong0Larry W. Baum1Justin D. Tubbs2Rui Ye3Lu Hua Chen4Tian Wu5Se-Fong Hung6Chun-Pan Tang7Ting-Pong Ho8Robert Moyzis9James Swanson10Chi-Chiu Lee11Pak C. Sham12Patrick W. L. Leung13Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic UniversityDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychiatry, The Chinese University of Hong KongKwai Chung HospitalDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Biological Chemistry, University of California, IrvineDepartment of Pediatrics, University of California, IrvineDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Psychology, The Chinese University of Hong KongAbstract 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.https://doi.org/10.1186/s11689-025-09626-4ADHDCommon variantLow-frequency / rare variantCerebellumLate-infancyImmune response |
| spellingShingle | Yuanxin Zhong Larry W. Baum Justin D. Tubbs Rui Ye Lu Hua Chen Tian Wu Se-Fong Hung Chun-Pan Tang Ting-Pong Ho Robert Moyzis James Swanson Chi-Chiu Lee Pak C. Sham Patrick W. L. Leung Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD Journal of Neurodevelopmental Disorders ADHD Common variant Low-frequency / rare variant Cerebellum Late-infancy Immune response |
| title | Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| title_full | Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| title_fullStr | Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| title_full_unstemmed | Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| title_short | Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD |
| title_sort | common and rare variant analyses implicate late infancy cerebellar development and immune genes in adhd |
| topic | ADHD Common variant Low-frequency / rare variant Cerebellum Late-infancy Immune response |
| url | https://doi.org/10.1186/s11689-025-09626-4 |
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