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[Preprint]. 2025 Sep 26:2025.09.26.25335972.
doi: 10.1101/2025.09.26.25335972.

Genome-wide association study of adolescent-onset depression

Poppy Z Grimes  1 , Brittany L Mitchell  2   3   4 , Katherine N Thompson  5 , Qingkun Deng  1 , Xueyi Shen  1 , Jareth C Wolfe  1 , Jodi T Thomas  2   3 , Robyn E Wootton  6   7   8   9 , Daniel E Adkins  10   11 , Saranya Arirangan  5 , Elham Assary  12 , Chris Chatzinakos  13 , Charlotte A Dennison  14   15 , Swathi Hassan Gangaraju  16 , Andreas Jangmo  17 , Yeongmi Jeong  5 , Siim Kurvits  18 , Qingqin S Li  19   20 , Ehsan Motazedi  21 , Joonas Naamanka  22   23 , Thuy-Dung Nguyen  24 , Ilja M Nolte  25 , Vanessa K Ota  26   27 , Joëlle A Pasman  24 , Mina Shahisavandi  28   29 , Amy Shakeshaft  14   30 , John R Shorter  31 , Chloe Slaney  32 , Martin Tesli  33 , Carol A Wang  34   35 , Uxue Zubizarreta-Arruti  36   37   38   39 ; PGC MDD Working Group; GLAD+; NIHR BioResource; Silvia Alemany  36   37   39 , Ole A Andreassen  40 , Helga Ask  8 , Sintia I Belangero  26   27 , Rosa Bosch  37   41   42 , Gerome Breen  12   43 , Rodrigo A Bressan  27 , Alfonso Buil  44 , Enda M Byrne  16 , Miquel Casas  42   45   46   47 , William E Copeland  48 , Thalia C Eley  12   43 , Laurie J Hannigan  7   8 , Catharina A Hartman  49 , Alexandra Havdahl  50   51   52 , Ian B Hickie  53 , Golam M Khandaker  32   54 , Kelli Lehto  18 , Hermine Maes  55   56 , Nicholas G Martin  2 , Alexander Neumann  28 , Albertine J Oldehinkel  49 , Pedro M Pan  27 , Hong Pan  57   58 , Craig E Pennell  34   35 , Roseann E Peterson  59 , Alina Rodriguez  57   60   61   62 , Giovanni A Salum  63   64 , Tanja Gm Vrijkotte  21   65 , Robbee Wedow  5   66 , Andrew Jo Whitehouse  67 , Anita Thapar  14   15 , Henrik Larsson  24   68 , Christel M Middeldorp  16   65   69   70 , Andrew McIntosh  1 , Mark J Adams  1 , Yi Lu  24 , Heather C Whalley  1 , Alex Sf Kwong  1   71
Affiliations

Genome-wide association study of adolescent-onset depression

Poppy Z Grimes et al. medRxiv. .

Abstract

Adolescent depression is a heritable psychiatric condition with rising global prevalence and severe long-term outcomes, yet its biological underpinnings remain poorly understood. We conducted the first genome-wide association study of adolescent-onset depression, comprising 102,428 cases (diagnosis or clinical symptom thresholds) and 286,911 controls, including diverse ancestries. Cross-ancestry meta-analysis identified 52 independent variants across 17 loci; European-only analysis found 61 variants at 29 loci, with a SNP-based heritability of 9.8%. Comparative analyses revealed two genes unique to adolescent-onset versus lifetime depression, enriched in neuronal subtypes, and two genes as potential drug repurposing targets. Polygenic scores were associated with adolescent-onset depression across ancestries, persistent depression trajectories, more severe outcomes, as well as reduced cortical volume, surface area and white matter integrity. Genetic correlation and Mendelian randomisation analyses support shared genetic liability and causal links with early puberty and modifiable health and behavioural risk factors. These findings uncover novel genetic loci and refine biological pathways underlying adolescent-onset depression, revealing age-specific mechanisms and early intervention opportunities.

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Conflict of interest statement

Conflicts of Interest Robbee Wedow is a research fellow at AnalytiXIN, which is a consortium of health-data organizations, industry partners and university partners in Indiana primarily funded through the Lilly Endowment, IU Health and Eli Lilly and Company. Ian Hickie holds a 3.2% equity share in Innowell Pty Ltd that is focused on digital transformation of mental health services. Pedro M Pan received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot. Qingqin Li was an employee of Janssen Research & Development, LLC, when this work was conducted and held stocks of Johnson & Johnson, the parental company of Janssen Research & Development, LLC. There is no conflict of interest other than salary received from the company. Henrik Larsson reports receiving grants from TAKEDA and Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. Henrik Larsson is editor-in-chief of JCPP Advances.

Figures

Figure 1.
Figure 1.. Miami plot of the cross-ancestry (top panel) and European (bottom panel) GWAS meta-analysis of adolescent-onset depression.
The autosomal SNP association strength in the meta-analyses is indicated by −log10(p) value on the y-axis. Genome-wide significant loci are depicted as red diamonds.
Figure 2.
Figure 2.. GenomicSEM path diagram showing genetic loadings of adolescent-onset depression phenotype ascertainment on a latent factor.
pG = genetic common factor, register-based = register-based early-onset diagnosis, prospective = prospectively self-reported, retrospective = retrospectively self-reported. Numbers represent standardised loadings with standard errors in brackets. The clinical phenotype loading was fixed to 1 as the reference. Self-directed arrows indicate variance of pG or the residual variances of each phenotype (u).
Figure 3.
Figure 3.. Expression patterns of BCL11B and MAP7D1 across neuronal subtypes in adolescent brain tissue.
Violin plots show the distribution of expression levels for BCL11B (a) and MAP7D1 (b) across three broad cell classes: inhibitory neurons (red), non-neuronal cells (grey), and excitatory neurons (blue). Panels (c) and (d) depict expression of BCL11B and MAP7D1, respectively, across 15 specific brain cell subtypes (major clusters). The y-axis represents the log normalised expression level for each cell.
Figure 4.
Figure 4.. Genetic correlation results for the main meta-analysis with a range of psychiatric and non-psychiatric traits.
Point estimates represent the genetic correlation value and error bars show 95% confidence intervals. All genetic correlations were significant after accounting for FDR, except the genetic correlation for intelligence.
Figure 5.
Figure 5.. Bi-directional Mendelian randomization (MR) between traits and adolescent-onset depression on the beta/log odds scale.
a, MR estimates for the effect of traits on adolescent-onset depression. For ‘No Physical Activity’, the upper 95% CI for the IVW extends to 7.742. b, MR estimates for the effect of adolescent-onset depression on traits. * indicates that the IVW method was significant at the FDR level, and the effect size was in the same direction for both the Weighted Median and the Weighted Mode methods. IVW: inverse-variance weighted method. WMedian: weighted median method. WMode: weighed mode method. MR Egger intercepts are given in Supplementary Table 18.
Figure 6.
Figure 6.. Polygenic score prediction across psychiatric, development and structural brain phenotypes.
a, Meta-analysed effect (odds ratio) of the cross-ancestry PGS on adolescent-onset depression case-status in the ABCD-US and Add Health cohorts for African, American-admixed, and European ancestries (95% confidence interval). b, Cross-ancestry PGS association with structural brain features in the ABCD-US study. Bars plotted on the y-axis represent the standardised regression coefficients with 95% confidence interval error bars. c, Cross-ancestry PGS association with regional brain features in the ABCD-US study. The y-axis represents the within-modality FDR corrected (q < 0.05) standardised regression coefficients with 95% confidence intervals. Features are split by imaging modalities plotted along the x-axis. Solid dots represent features significantly associated with PGS after FDR correction. d, European PGS effects (odds ratio) on adolescent psychiatric traits in ALSPAC (95% confidence interval). e, PGS association with depression symptom trajectories in the ALSPAC cohort between the ages of 10 and 28 years (11 occasions). The reference category is the low trajectory for relative risk ratios (RRR).
See this image and copyright information in PMC

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