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Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility

Molecular Psychiatry volume 26, pages 2277–2285 (2021)Cite this article

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Abstract

The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = −2.701; p = 0.0069); rs1947274 A allele (Z score = −2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = −0.822; p = 0.4109); and rs2345039 C allele (Z score = −1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3’s role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD.

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Fig. 1
Fig. 2: Forest plots showing the association analysis of ADGRL3 SNPs.
Fig. 3: Forest plots showing the association analysis of ADGRL3 SNPs.

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Acknowledgements

The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and Fundo de Incentivo à Pesquisa e Eventos—Hospital de Clínicas de Porto Alegre (FIPE/HCPA, Brazil) for financial support. The authors also thank Han Jun Jin from the Department of Nanobiomedical Science, Dankook University in South Korea for the provided clarifications.

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Authors and Affiliations

  1. Department of Genetics, Universidade Federal do Rio Grande do Sul, Caixa Postal 15053, Porto Alegre, RS, 91501-970, Brazil

    E. M. Bruxel, G. C. Akutagava-Martins, D. B. Kappel, C. H. D. Bau & M. H. Hutz

  2. ADHD Outpatient Program (PRODAH) and Developmental Psychiatry Program, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    E. M. Bruxel, C. R. Moreira-Maia, G. C. Akutagava-Martins, L. A. Rohde & M. H. Hutz

  3. College of Medicine, Universidade Federal de Mato Grosso, Cuiabá, Brazil

    G. C. Akutagava-Martins

  4. Bioinformatics Core Research Group, Deakin University, Geelong, VIC, Australia

    T. P. Quinn

  5. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    M. Klein, B. Franke & N. R. Mota

  6. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    M. Klein

  7. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    B. Franke & N. R. Mota

  8. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    M. Ribasés, P. Rovira & C. Sánchez-Mora

  9. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain

    M. Ribasés & C. Sánchez-Mora

  10. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    M. Ribasés, P. Rovira & C. Sánchez-Mora

  11. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    M. Ribasés & C. Sánchez-Mora

  12. ADHD Outpatient Program (PRODAH - A), Adult Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    D. B. Kappel, N. R. Mota, E. H. Grevet & C. H. D. Bau

  13. Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    E. H. Grevet

  14. Grupo de Investigación en Psiquiatría (GIPSI), Instituto de Investigaciones Medicas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia

    M. Arcos-Burgos

  15. National Institute of Developmental Psychiatry for Children and Adolescents, Porto Alegre, Brazil

    L. A. Rohde

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  1. E. M. Bruxel
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Contributions

EMB, GCAM, CRMM, LAR, and MHH conceived and designed the study. MK, BF, MR, DBK, NRM, EHG, CHDB, and MAB contributed with data. EMB, GCAM, CRMM, PR, and TPQ conducted statistical analyses and wrote the first draft of the manuscript. PR provided SNP-based and gene-based results for ADGRL3 on ADHD in children and on persistent ADHD in adults from their GWAS-MA [19]. LAR and MHH provided funding for the project. All coauthors provided critical feedback on the manuscript, suggested additional analyses, and critical revisions, and edited the manuscript for clarity and precision. All authors contributed to and have approved the final manuscript.

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Correspondence to M. H. Hutz.

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Conflict of interest

CRMM receives financial research support from the government agency: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). CRMM received fees for the development of educational materials for Libbs, Novartis, and Pfizer. He has served as a consultant and served on the speakers’ bureau of Shire. Libbs, Novartis, and Shire make products for the treatment of ADHD. CRMM received travel, accommodation, and registration support to the fourth and fifth World Congress on ADHD from the World Federation of ADHD. EHG was on the speaker’s bureau for Novartis and Shire, and Shire’s national and international advisory boards for the last 3 years. He also received travel awards (air tickets and hotel accommodations) for participating in two psychiatric meetings from Shire and Novartis. LAR has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Eli Lilly and Co., Janssen, Medice, Novartis and Shire. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LAR have received unrestricted educational and research support from the following pharmaceutical companies: Eli Lilly and Co., Janssen, Novartis, and Shire. LAR has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA and from Novartis to take part of the 2015 WFADHD congresses. MHH receives financial research support from the Brazilian governmental agency: CNPq. EMB and GCAM have received financial research support from CNPq. CHDB and DBK have received financial support from the following Brazilian agencies: CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and HCPA (FIPE-HCPA). BF has received educational speaking fees from Shire and Medice. She also is supported by the personal Vici grant from the Netherlands Organisation for Scientific Research (NWO). PR is a recipient of a predoctoral fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya, Spain (2016FI_B 00899). TPQ, MK, MR, NRM, and MAB have no competing interests.

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Bruxel, E.M., Moreira-Maia, C.R., Akutagava-Martins, G.C. et al. Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility. Mol Psychiatry 26, 2277–2285 (2021). https://doi.org/10.1038/s41380-020-0673-0

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