颜林林
(2025-09-27 13:13):
#paper doi:10.1101/2025.09.26.25335972, medRxiv, 2025, Genome-wide association study of adolescent-onset depression. 这又是一篇超大规模人群的GWAS（全基因组关联分析）研究，研究对象是青少年抑郁症。整个分析的入组人群，包括 102,428 例患者 和 286,911 例对照，来自 12 个国家的共计 25 个队列。看起来似乎很有代表性，号称跨种族（Cross-ancestry），但从数据构成看，其 95% 以上个体，其实仅来自欧洲的单个队列。除了传统的 GWAS 分析外，为了提高研究的整体价值，这项研究揉进了 eQTL、药物靶点筛选、多基因评分和孟德尔随机化等分析，虽说用于这些分析的样本量远不及 GWAS 本身的样本量，但这些以基因水平为核心的“下游模块”，确实把 SNP 信号直接翻译成了可解释的生物学语言：比如 eQTL 与 MAGMA 把 61 个 lead SNP 映射到 23 个显著基因，DrugBank 对接把 GABBR1、PDE4B 推成“老药新用”候选。虽然文章目前仅是预发表草稿，内容和逻辑还远不够完善，但这些整合不同水平分析结果来讲故事的思路尝试，还是挺值得学习的。
medRxiv,
2025-9-26.
DOI: 10.1101/2025.09.26.25335972
Genome-wide association study of adolescent-onset depression
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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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