TY - JOUR
T1 - Genome-wide association study of adolescent-onset depression
AU - Grimes, Poppy Z
AU - Mitchell, Brittany L
AU - Thompson, Katherine N
AU - Deng, Qingkun
AU - Shen, Xueyi
AU - Wolfe, Jareth C
AU - Thomas, Jodi T
AU - Wootton, Robyn E
AU - Adkins, Daniel E
AU - Arirangan, Saranya
AU - Assary, Elham
AU - Chatzinakos, Chris
AU - Dennison, Charlotte A
AU - Gangaraju, Swathi Hassan
AU - Jangmo, Andreas
AU - Jeong, Yeongmi
AU - Kurvits, Siim
AU - Li, Qingqin S
AU - Motazedi, Ehsan
AU - Naamanka, Joonas
AU - Nguyen, Thuy-Dung
AU - Nolte, Ilja M
AU - Ota, Vanessa K
AU - Pasman, Joëlle A
AU - Shahisavandi, Mina
AU - Shakeshaft, Amy
AU - Slaney, Chloe
AU - PGC MDD Working Group
AU - Havdahl, Alexandra
AU - Khandaker, Golam M
AU - McIntosh, Andrew
AU - Adams, Mark J.
AU - Lu, Yi
AU - Whalley, Heather C
AU - Kwong, Alex Sf
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
U2 - 10.1101/2025.09.26.25335972
DO - 10.1101/2025.09.26.25335972
M3 - Article (Academic Journal)
C2 - 41040734
JO - medRxiv
JF - medRxiv
ER -