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Cited by 144Genomic variations and chromosomal abnormalitiesGenetic Associations and EpidemiologyGenomics and Rare Diseases

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Association of Rare Copy Number Variants With Risk of Depression

Open access
Kendall, Kimberley Marie, Rees, Elliott, Bracher-Smith, Matthew, Legge, Sophie, Riglin, Lucy, Zammit, Stanley, O’Donovan, Michael Conlon, Owen, Michael John, Jones, Ian, Kirov, George, Walters, James Tynan Rhys·2019·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2019.0566PMC PMC6583866
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Abstract

Importance: The role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear. Objective: To examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression. Design, Setting, and Participants: This case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018. Exposures: CNV carrier status. Main Outcomes and Measures: For the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression. Results: Copy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression. Conclusions and Relevance: Neurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

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Figure 1. Flowchart of Study Methods ASD indicates autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; BPAD, bipolar affective disorder; CNV, copy number variant; IBD, identity by descent; ID, intellectual disability; QC, quality control.
Figure 1. Flowchart of Study Methods ASD indicates autism spectrum disorder; ADHD, attention-deficit/hyperactivity disorder; BPAD, bipolar affective disorder; CNV, copy number variant; IBD, identity by descent; ID, intellectual disability; QC, quality control.CC BY · PubMed Central
Figure 2. Analyses of Individual Neurodevelopmental Copy Number Variants (CNVs) for Association With Self-reported Depression Del indicates deletion; dup, duplication. aCNVs that survived Bonferroni correction for 53 tests. bResults with P < .05. Schizophrenia CNVs are shown as light blue. All CNVs fall within the neurodevelopmental CNV group. The dashed line indicates an odds ratio of 1.
Figure 2. Analyses of Individual Neurodevelopmental Copy Number Variants (CNVs) for Association With Self-reported Depression Del indicates deletion; dup, duplication. aCNVs that survived Bonferroni correction for 53 tests. bResults with P < .05. Schizophrenia CNVs are shown as light blue. All CNVs fall within the neurodevelopmental CNV group. The dashed line indicates an odds ratio of 1.CC BY · PubMed Central
Figure 3. Association Between Neurodevelopmental Copy Number Variants (CNVs) and Depression The numbers shown are estimates for direct and indirect effects of each of the 5 variables (educational attainment, physical health, social deprivation, smoking status, and alcohol consumption), calculated using structural equation modeling in the lavaan package in R (R Foundation for Statistical Computing).36 Full results, including SEs and P values, are shown in eTable 3 in the Supplement.
Figure 3. Association Between Neurodevelopmental Copy Number Variants (CNVs) and Depression The numbers shown are estimates for direct and indirect effects of each of the 5 variables (educational attainment, physical health, social deprivation, smoking status, and alcohol consumption), calculated using structural equation modeling in the lavaan package in R (R Foundation for Statistical Computing).36 Full results, including SEs and P values, are shown in eTable 3 in the Supplement.CC BY · PubMed Central

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Authors
Kendall, K. M., Rees, E., Bracher-Smith, M., Legge, S., Riglin, L., Zammit, S., O’Donovan, M. C., Owen, M. J., Jones, I., Kirov, G., & Walters, J. T. R.
Affiliations
  • Cardiff University (GB)
  • MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales, United Kingdom
  • University of Bristol (GB)
Corresponding author
Walters, James Tynan Rhys
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2019-08-01
Volume
76
Issue
8
Pages
818
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2019.0566
PMC
PMC6583866
OpenAlex
W2938501314
Cited by
144
References
44
Citations by year
2026: 10 · 2025: 20 · 2024: 20 · 2023: 16 · 2022: 23 · 2021: 21 · 2020: 29 · 2019: 4
FWCI
11.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Explore Bristol Research (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (201171/Z/16/Z)
  • MQ: Transforming Mental Health (MQDS16/36)
  • Medical Research Council (MR/L011794/1, MR/P005748/1, MR/L010305/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
copy number variation, depression, rare variants, neurodevelopmental disorders, genetic risk factors, mental illness, UK Biobank, antidepressant prescribing, European ancestry, alcohol and tobacco use, educational attainment, social deprivation
MeSH terms
Adult, Aged, Alcohol Drinking, Depressive Disorder, Educational Status, Female, United Kingdom, Health Status, Humans, Male, Middle Aged, Psychosocial Deprivation, Risk, Severity of Illness Index, Smoking, Case-Control Studies, Biological Specimen Banks, Genetic Predisposition to Disease, DNA Copy Number Variations, Neurodevelopmental Disorders

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