Genetic markers for depressive disorders with earlier age at onset

Kang, Hyun-Kyu; Kim, Ki Tae; Park, Yoomi; Yoo, Kyung Hun; Kim, Ju Wan; Lee, Ju‐Yeon; Kim, Sung Wan; Shin, Il‐Seon; Kim, Ju Han; Kim, Jae Min

doi:10.1016/j.pnpbp.2020.110176

Cited by 8 publications

(4 citation statements)

References 72 publications

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“…Last, the summary statistics from the GWAS are based on genetic risk for adult diagnoses. Some studies indicate that other variants may contribute to earlier onset of disorder (Kang et al, 2021; Power et al, 2017; Power et al, 2012; Harder et al, 2022), but this is still not well established. In the future, as GWAS on child and adolescents will become available, our findings should be replicated with PGS derived from child and adolescent diagnosis alone and combined with diagnosis at an older age.…”

Section: Discussionmentioning

confidence: 99%

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

Bakken,

Parker,

Hannigan

et al. 2023

Preprint

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BackgroundSymptoms related to mood and anxiety disorders often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for mood and anxiety disorders influence trajectories of childhood emotional and behavioral difficulties, and if specific developmental patterns associate with higher genetic liability for these disorders.MethodsThis study uses data from a genotyped sample of children (n= 54,839) from the Norwegian Mother, Father and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR).ResultsAssociations between PGSDEP, PGSANXand PGSNEUR, and emotional and behavioral difficulties in childhood were developmentally stable rather than age specific. Higher PGSANXand PGSDEPwere associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles. All PGS were associated with probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBDwas uniquely associated with a single developmental profile.ConclusionsOur findings indicate that genetic risk for mood disorders and related traits contribute to a more rapidly increasing and higher overall burden of emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. These findings of associations between childhood trajectories and symptom profiles and genetic and clinical susceptibility for mental disorders, may form the basis for more targeted early interventions.

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Section: Discussionmentioning

confidence: 99%

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

Bakken,

Parker,

Hannigan

et al. 2023

Preprint

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“…Tudor Constantin Badea, Transilvania University of Brașov, Romania Vaz et al 10.3389/fnins.2023.1205653 Frontiers in Neuroscience 02 frontiersin.org (Kang et al, 2021), cerebral palsy (McMichael et al, 2014), anxiety (Nivard et al, 2014), epilepsy (van Rootselaar et al, 2017), and schizophrenia (Vrijenhoek et al, 2008). Even though it is not entirely understood how heterozygous loss or expression of CTNND2 variants result in such disorders, research done in in vitro systems, such as neurons in culture, or animal models, have provided with some understanding of the possible role of CTNND2 in neurogenesis.…”

Section: Open Access Edited Bymentioning

confidence: 99%

“…Interestingly, individuals in whom CTNND2 was included in the deleted region showed more severe neurological symptoms ( Medina et al, 2000 ; Mainardi et al, 2001 ; Sardina et al, 2014 ). Genetic changes affecting CTNND2 , both structural variants and single nucleotide variants, have been associated with autism-spectrum disorder ( Girirajan et al, 2013 ; Turner et al, 2015 ; Miller et al, 2020 ; Tuncay et al, 2022 ), intellectual disability with or without dyslexia-like learning difficulties ( Belcaro et al, 2015 ; Hofmeister et al, 2015 ), neurodevelopmental delay ( Asadollahi et al, 2014 ), attention deficit hyperactivity disorder or ADHD ( Adegbola et al, 2020 ), depression ( Kang et al, 2021 ), cerebral palsy ( McMichael et al, 2014 ), anxiety ( Nivard et al, 2014 ), epilepsy ( van Rootselaar et al, 2017 ), and schizophrenia ( Vrijenhoek et al, 2008 ). Even though it is not entirely understood how heterozygous loss or expression of CTNND2 variants result in such disorders, research done in in vitro systems, such as neurons in culture, or animal models, have provided with some understanding of the possible role of CTNND2 in neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of ctnnd2b affects neuronal differentiation and behavior in zebrafish

et al. 2023

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Delta-catenin (CTNND2) is an adhesive junction associated protein belonging to the family of p120 catenins. The human gene is located on the short arm of chromosome 5, the region deleted in Cri-du-chat syndrome (OMIM #123450). Heterozygous loss of CTNND2 has been linked to a wide spectrum of neurodevelopmental disorders such as autism, schizophrenia, and intellectual disability. Here we studied how heterozygous loss of ctnnd2b affects zebrafish embryonic development, and larvae and adult behavior. First, we observed a disorganization of neuronal subtypes in the developing forebrain, namely the presence of ectopic isl1-expressing cells and a local reduction of GABA-positive neurons in the optic recess region. Next, using time-lapse analysis, we found that the disorganized distribution of is1l-expressing forebrain neurons resulted from an increased specification of Isl1:GFP neurons. Finally, we studied the swimming patterns of both larval and adult heterozygous zebrafish and observed an increased activity compared to wildtype animals. Overall, this data suggests a role for ctnnd2b in the differentiation cascade of neuronal subtypes in specific regions of the vertebrate brain, with repercussions in the animal’s behavior.

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“…Several genome-wide association studies (GWAS) and one exome-wide association study have been performed to understand the genomics of MDD specific to age at onset [ 8 , 12 , 13 , 14 , 15 ]. Collectively, and in conjunction with polygenic risk analyses, these studies suggest that earlier-onset MDD may share greater genetic overlap with schizophrenia, bipolar disorders, and attention deficit/hyperactivity disorder (ADHD) than later onset [ 8 , 12 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder

Grant

Barreto

Kumar

et al. 2022

JPM

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Age at depressive onset (AAO) corresponds to unique symptomatology and clinical outcomes. Integration of genome-wide association study (GWAS) results with additional “omic” measures to evaluate AAO has not been reported and may reveal novel markers of susceptibility and/or resistance to major depressive disorder (MDD). To address this gap, we integrated genomics with metabolomics using data-driven network analysis to characterize and differentiate MDD based on AAO. This study first performed two GWAS for AAO as a continuous trait in (a) 486 adults from the Pharmacogenomic Research Network-Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS), and (b) 295 adults from the Combining Medications to Enhance Depression Outcomes (CO-MED) study. Variants from top signals were integrated with 153 p180-assayed metabolites to establish multi-omics network characterizations of early (<age 18) and adult-onset depression. The most significant variant (p = 8.77 × 10−8) localized to an intron of SAMD3. In silico functional annotation of top signals (p < 1 × 10−5) demonstrated gene expression enrichment in the brain and during embryonic development. Network analysis identified differential associations between four variants (in/near INTU, FAT1, CNTN6, and TM9SF2) and plasma metabolites (phosphatidylcholines, carnitines, biogenic amines, and amino acids) in early- compared with adult-onset MDD. Multi-omics integration identified differential biosignatures of early- and adult-onset MDD. These biosignatures call for future studies to follow participants from childhood through adulthood and collect repeated -omics and neuroimaging measures to validate and deeply characterize the biomarkers of susceptibility and/or resistance to MDD development.

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Genetic markers for depressive disorders with earlier age at onset

Cited by 8 publications

References 72 publications

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders

Loss of ctnnd2b affects neuronal differentiation and behavior in zebrafish

Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder

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