Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals

Akingbuwa, Wonuola A.; Hammerschlag, Anke R.; Jami, Eshim S; Allegrini, Andrea; Karhunen, Ville; Sallis, Hannah M; Ask, Helga; Askeland, Ragna Bugge; Baselmans, Bart M. L.; Diemer, Elizabeth W; Hagenbeek, Fiona A.; Havdahl, Alexandra; Hottenga, Jouke‐Jan; Mbarek, Hamdi; Rivadeneira, Fernando; Tesli, Martin; Beijsterveldt, Catharina E. M. van; Breen, Gerome; Lewis, Cathryn M.; Thapar, Anita; Boomsma, Dorret I.; Kuja‐Halkola, Ralf; Reichborn‐Kjennerud, Ted; Magnus, Per; Rimfeld, Kaili; Ystrøm, Eivind; Järvelin, Marjo‐Riitta; Lichtenstein, Paul; Lundström, Sebastian; Munafò, Marcus R.; Plomin, Robert; Tiemeier, Henning; Nivard, Michel G.; Bartels, Meike; Middeldorp, Christel M.

doi:10.1001/jamapsychiatry.2020.0527

Cited by 66 publications

(68 citation statements)

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“…Strong genetic correlations (|rg| > 0.7) with adult depression, anxiety, neuroticism, and the wellbeing spectrum were of note, and suggest a substantial shared genetic etiology between childhood internalising symptoms and adult internalising disorders and related traits, that has also been observed in previous studies (44)(45)(46). However, the observed correlations with adult internalising disorders were partial rather than complete, indicating that from a developmental perspective, childhood and adolescent internalising symptoms are not genetically identical to adult depression or anxiety.…”

Section: Discussionsupporting

confidence: 78%

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Jami

Allegrini

et al. 2020

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Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses showed rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Gene-based analyses showed significant associations with three genes: WNT3 (p=1.13×10-06), CCL26 (p=1.88×10-06), and CENPO (p=2.54×10-06). Of these, WNT3 was previously associated with neuroticism, with which INToverall also shared a strong genetic correlation (rg=0.76). Genetic correlations were also observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Overall, childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could explain both the persistence of internalising symptoms over time, and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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Section: Discussionsupporting

confidence: 78%

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Jami

Allegrini

et al. 2020

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“…PRS have been used to assess the impact of genetic contributions on depressive phenotypes at various ages. For example, PRS of MDD have recently been associated with self-or maternal-reported childhood psychopathologies, such as internalizing symptoms from 7 to 16 (Akingbuwa et al, 2020), as well as self-reported adolescent depressive symptom trajectories from ages 10 to 24 (Kwong et al, 2019;Rice et al, 2018). Although these studies have provided important new insights into All rights reserved.…”

Section: Most Of Them Have Characterized Between Three and Six Primarmentioning

confidence: 99%

“…https://doi.org/10.1101/2020.03.02.19007088 doi: medRxiv preprint 6 the genetic underpinnings of depression, they collectively have two main limitations. First, most have focused on narrow ages range, with only one study including children younger than 10 years old (Akingbuwa et al, 2020). Thus, there has been limited attention to the earliest manifestations of depressive symptoms, which is a shortcoming as some symptoms can emerge as early as preschool (Whalen et al, 2017).…”

Section: Most Of Them Have Characterized Between Three and Six Primarmentioning

confidence: 99%

Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence

Lussier

Hawrilenko

Wang

et al. 2020

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Background: Depression that onsets during childhood and adolescence is associated with worse illness course and outcomes. However, the genetic factors that influence risk for early-onset depression remain mostly unknown. Using data collected over thirteen years, we examined whether polygenic risk scores (PRS) capturing genetic risk for major depressive disorder (MDD) were associated with early-onset depressive symptoms, as assessed from childhood to adolescence. Methods: Data came from the Avon Longitudinal Study of Parents and Children, a prospective, longitudinal birth cohort (analytic sample=7,308 youth). We analyzed the relationship between genetic susceptibility to depression and three time-dependent measures of depressive symptoms across ages 4-16.5 (trajectories, onset, and cumulative burden of symptoms). Trajectories were constructed using a growth mixture model with structured residuals. Symptom onset and cumulative burden were assessed using the intercept and area under the trajectory curves, respectively. PRS were generated using MDD summary statistics from the Psychiatric Genomics Consortium. We used MAGMA to identify gene-level associations with these measures. Results: Youth were classified into six classes of depressive symptom trajectories: high/renitent (26.5% of youth), high/reversing (5.8%), childhood decrease (6.1%), late childhood peak (3%), adolescent spike (2.5%), and minimal symptoms (56.1%). PRS could discriminate between youth in the "high" classes compared to the minimal symptoms and childhood decrease classes. Two genes (SIX5; DMPK) were nominally associated with both onset and cumulative burden. Conclusions: This study highlights a role for genetic factors in shaping depressive symptoms across childhood and adolescence, particularly among youths with generally high or low symptoms, regardless of age-independent responding.

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“…However, despite substantial twin heritability (a mean of 60%; Cheesman et al, 2017), GPS heritabilities are modest for childhood behaviour problems such as autism spectrum disorder (2.5%; Grove et al, 2019) and ADHD (3.3%; de Bode et al, 2020). In a recent study, GPS prediction of childhood ADHD symptoms, internalizing and social problems was reported to be much lower for adult-based GPS of major depression (0.2%), neuroticism (0.1%), insomnia (0.05%) and subjective wellbeing (0.06%) (Akingbuwa et al, 2020). A recent GWA study of childhood and adolescence internalizing symptoms predicted 0.4% of the variance in internalizing at age 7 and 0.03% at ages 13-18 (Jami et.…”

mentioning

confidence: 99%

“…To test the hypothesis that the multi-GPS approach will yield greater GPS heritability than the single-GPS approach, we assessed the joint prediction of 15 GPS in penalised regression models with out-of-sample evaluation of prediction accuracy (multi-GPS) (Zou & Hastie, 2005). In addition to GPS for childhood behaviour problems (ADHD; autism spectrum disorder), we included GPS derived from the much larger GWA studies of adult psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder and traits such as neuroticism, well-being and risk-taking as they have been shown to predict a variety of childhood phenotypes, including psychopathology (Allegrini et al, 2020b) and behaviour problems (Akingbuwa et al, 2020).…”

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confidence: 99%

Using DNA to predict behaviour problems from preschool to adulthood

Gidziela

Rimfeld

Malanchini

et al. 2021

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Background: One goal of the DNA revolution is to predict problems in order to prevent them. We tested here if the prediction of behaviour problems from genome-wide polygenic scores (GPS) can be improved by creating composites across ages and across raters and by using a multi-GPS approach that includes GPS for adult psychiatric disorders as well as for childhood behaviour problems. Method: Our sample included 3,065 genotyped unrelated individuals from the Twins Early Development Study who were assessed longitudinally for hyperactivity, conduct, emotional problems and peer problems as rated by parents, teachers and children themselves. GPS created from 15 genome-wide association studies were used separately and jointly to test the prediction of behaviour problems composites (general behaviour problems, externalizing and internalizing) across ages (from age 2 to age 21) and across raters in penalized regression models. Based on the regression weights, we created multi-trait GPS reflecting the best prediction of behaviour problems. We compared GPS prediction to twin heritability using the same sample and measures. Results: Multi-GPS prediction of behaviour problems increased from less than 2% of the variance for observed traits to up to 6% for cross-age and cross-rater composites. Twin study estimates of heritability mirrored patterns of multi-GPS prediction as they increased from less than 40% to up to 83%. Conclusions: The ability of GPS to predict behaviour problems can be improved by using multiple GPS, cross-age composites and cross-rater composites, although the effect sizes remain modest, up to 6%. Our results can be used in any genotyped sample to create multi-trait GPS predictors of behaviour problems that will be more predictive than polygenic scores based on a single age, rater or GPS.

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Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals

Cited by 66 publications

References 80 publications

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence

Using DNA to predict behaviour problems from preschool to adulthood

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Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals

Cited by 66 publications

References 80 publications

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms

Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence

Using DNA to predict behaviour problems from preschool to adulthood

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Product

Resources

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Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals