Association of Rare Copy Number Variants With Risk of Depression

Kendall, Kimberley; Rees, Elliott; Bracher-Smith, Matthew; Legge, Sophie E.; Riglin, Lucy; Zammit, Stanley; O’Donovan, Michael; Jones, Ian; Kirov, George; Walters, James

doi:10.1001/jamapsychiatry.2019.0566

Cited by 105 publications

(97 citation statements)

References 45 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our non-significant results for MDD are inconsistent with a recent UK population study of middle-aged adults, which found weak evidence to suggest that rare neuropsychiatric copy number variants may be associated with depression in females. 25 On the other hand, another study of this UK population found no gender interaction with polygenic risk scores for ADHD and risk of anxiety, MDD and bipolar disorders, 26 which is consistent with our results for MDD and bipolar disorders but inconsistent with the results for anxiety. Our results suggest that the age of diagnosed individuals may have an impact on the observation of an association between familial/genetic risks and gender differences in psychiatric disorders.…”

Section: Discussionsupporting

confidence: 66%

Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population

et al. 2020

View full text Add to dashboard Cite

Background Many psychiatric disorders show gender differences in prevalence. Recent studies suggest that female patients diagnosed with anxiety and depression carry more genetic risks related to attention-deficit hyperactivity disorder (ADHD) compared with affected males. Aims In this register-based study, we aimed to test whether female patients who received clinical diagnoses of anxiety, depressive, bipolar and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders, compared with diagnosed male patients. Method We analysed data from a record-linkage of several Swedish national registers, including 151 025 sibling pairs from 103 941 unique index individuals diagnosed with anxiety, depressive, bipolar or eating disorders, as well as data from 646 948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/neurodevelopmental disorders in index males and females. Results Female patients with anxiety disorders were more likely than affected males to have a brother with ADHD (odd ratio (OR) = 1.13, 95% CI 1.05–1.22). Results for broader neurodevelopmental disorders were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia (OR = 1.64, 95% CI 1.12–2.39). No significant associations were found in individuals with depressive, bipolar or eating disorders, or in cousins. Conclusions These results provide modest support for the possibility that familial/genetic risks for ADHD may show gender-specific phenotypic expression. Alternatively, there could be gender-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed gender differences in prevalence of ADHD and anxiety.

show abstract

Section: Discussionsupporting

confidence: 66%

Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Additionally, our data are consistent with previous observations that individuals with rare CNVs are at increased risk for depression. 63 These penetrance estimates (35%-70%) are comparable with some of the highest health risks associated with hereditary cancer and cardiovascular disorders, including BRCA1/2 (38%-87% lifetime risk for breast cancer), Lynch syndrome (52%-82% lifetime risk for colorectal cancers), and familial hypercholesterolemia (30%-50% risk for coronary event). 59,60,64 Genetic causes will increasingly inform NPD care by hastening diagnosis and treatment of developmental or psychiatric concerns (eg, schizophrenia with 22q11.2 deletions) and by monitoring for known medical risks (eg, kidney disease and maturity onset diabetes of the young with 17q12 deletions).…”

Section: Discussionmentioning

confidence: 78%

Identification of Neuropsychiatric Copy Number Variants in a Health Care System Population

et al. 2020

View full text Add to dashboard Cite

IMPORTANCE Population screening for medically relevant genomic variants that cause diseases such as hereditary cancer and cardiovascular disorders is increasing to facilitate early disease detection or prevention. Neuropsychiatric disorders (NPDs) are common, complex disorders with clear genetic causes; yet, access to genetic diagnosis is limited. We explored whether inclusion of NPD in population-based genomic screening programs is warranted by assessing 3 key factors: prevalence, penetrance, and personal utility. OBJECTIVE To evaluate the suitability of including pathogenic copy number variants (CNVs) associated with NPD in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, the frequency of 31 NPD CNVs was determined in patient-participants via exome data. Associated clinical phenotypes were assessed using linked electronic health records. Nine CNVs were selected for disclosure by licensed genetic counselors, and participants' psychosocial reactions were evaluated using a mixed-methods approach. A primarily adult population receiving medical care at Geisinger, a large integrated health care system in the United States with the only population-based genomic screening program approved for medically relevant results disclosure, was included. The cohort was identified from the Geisinger MyCode Community Health Initiative. Exome and linked electronic health record data were available for this cohort, which was recruited

show abstract

“…etrance is higher in individuals with these disorders. 39 Furthermore, CNVs in the UK Biobank have been associated with a range of outcomes, including cognitive performance 38,44 and depression, 45 adding strength to our findings of a lack of specificity for genetic risk of psychotic experiences. Several studies have demonstrated that psychopathologic conditions in the population are best described by a bifactor model with a common latent trait as well as specific traits, and that psychotic experiences index the more severe end of the common or shared trait.…”

Section: Discussionmentioning

confidence: 66%

Association of Genetic Liability to Psychotic Experiences With Neuropsychotic Disorders and Traits

et al. 2019

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance. OBJECTIVES To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences. DESIGN, SETTING AND PARTICIPANTS Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses. MAIN OUTCOMES AND MEASURES Genetic associations with psychotic experience phenotypes. RESULTS The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/ hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10 −4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10 −3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10 −8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10 −8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism-based heritability estimate (h 2 = 1.71%; 95% CI, 1.02%-2.40%). CONCLUSIONS AND RELEVANCE A large genetic association study of ...

show abstract

Association of Rare Copy Number Variants With Risk of Depression

Cited by 105 publications

References 45 publications

Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population

Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population

Identification of Neuropsychiatric Copy Number Variants in a Health Care System Population

Association of Genetic Liability to Psychotic Experiences With Neuropsychotic Disorders and Traits

Contact Info

Product

Resources

About