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A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder
Authors:Joanna Martin  Raymond K. Walters  Ditte Demontis  Manuel Mattheisen  S. Hong Lee  Elise Robinson  Isabell Brikell  Laura Ghirardi  Henrik Larsson  Paul Lichtenstein  Nicholas Eriksson
Affiliation:1. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden;2. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;3. Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden;4. School of Medical Sciences, Örebro University, Örebro, Sweden;5. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts;6. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts;7. 23andMe Inc., Mountain View, California;8. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York;9. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom;10. Lundbeck Foundation Initiative for Integrative Psychiatric Research [iPSYCH], Aarhus, Roskilde, Denmark;11. Centre for Integrative Sequencing [iSEQ], Aarhus University, Aarhus, Roskilde, Denmark;12. Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Roskilde, Denmark;13. National Centre for Register-Based Research, Aarhus University, Aarhus, Roskilde, Denmark;14. Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Roskilde, Denmark;15. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark;p. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;q. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark;r. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark;s. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark;t. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia;u. School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia;v. Centre for Population Health Research, School of Health Sciences and Sansom Institute of Health Research, University of South Australia, Adelaide, Australia;w. Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;x. K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway;1. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden;2. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;3. Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden;4. School of Medical Sciences, Örebro University, Örebro, Sweden;5. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts;6. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts;7. 23andMe Inc., Mountain View, California;8. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York;9. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom;10. Lundbeck Foundation Initiative for Integrative Psychiatric Research [iPSYCH], Aarhus, Roskilde, Denmark;11. Centre for Integrative Sequencing [iSEQ], Aarhus University, Aarhus, Roskilde, Denmark;12. Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Roskilde, Denmark;13. National Centre for Register-Based Research, Aarhus University, Aarhus, Roskilde, Denmark;14. Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Roskilde, Denmark;15. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark;p. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;q. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark;r. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark;s. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark;t. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia;u. School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia;v. Centre for Population Health Research, School of Health Sciences and Sansom Institute of Health Research, University of South Australia, Adelaide, Australia;w. Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;x. K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway
Abstract:

Background

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.

Methods

We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).

Results

Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15).

Conclusions

Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
Keywords:ADHD  Epidemiology  GWAS  Neurodevelopmental disorders  Polygenic risk score analysis  Sex bias
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