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PMID: 42472273 已发表 · aheadofprint 英语

Shared genetics between ADHD and reading/language abilities: Genome-wide correlations, stratified enrichment, cross-trait association, and mendelian randomization.

JCPP advances ·2026-07-18

Zhao J, Huang S, Liu W, Wang F, Qian H, Hu X

摘要

Attention-deficit/hyperactivity disorder (ADHD) and language/reading difficulties frequently co-occur. The extent of shared genetic architecture remains incompletely defined. We investigated genome-wide overlap between ADHD and four core skills: word reading, nonword reading, spelling, and phoneme awareness. We integrated genome-wide association study (GWAS) summary statistics from the Psychiatric Genomics Consortium for ADHD (38,691 cases; 186,843 controls) and from the GenLang Consortium for language-related traits (n = 13,633-33,959). We performed linkage disequilibrium score regression (LDSC) to estimate genetic correlations and stratified LDSC to identify enriched genomic annotations. Cross-trait meta-analyses were conducted using MTAG and CPASSOC to identify cross-trait association signals. Mendelian randomization (MR) was applied to assess potential directional relationships. Genome-wide genetic correlations were negative and significant between ADHD and each reading- and language-related trait (word reading rg = -0.35, p = 1.35 × 10-16; nonword reading rg = -0.28, p = 2.15 × 10-9; spelling rg = -0.38, p = 1.03 × 10-15; phoneme awareness rg = -0.28, p = 2.64 × 10-6). Partitioned heritability analysis using S-LDSC showed significant enrichment after Benjamini-Hochberg false discovery rate correction (BH-FDR), concentrated in conserved or constrained annotations such as Genomic Evolutionary Rate Profiling and phastCons. Cross-trait analyses (MTAG and CPASSOC) identified loci associated with ADHD and each skill, 6 for word reading, 7 for spelling, 7 for phoneme awareness, and 4 suggestive loci for nonword reading (dual-method p < 5 × 10-6); several map near neurodevelopmental genes including DCC, MEF2C, and ST3GAL3. Bidirectional MR findings were consistent with a potential directional contribution of ADHD genetic liability to poorer reading/language performance, with no clear evidence supporting the reverse direction under standard MR assumptions. ADHD and language/reading abilities share a substantial polygenic overlap with convergent signals in neuronal regulatory annotations. These genome-wide findings support a transdiagnostic framework linking attention and literacy-related skills, while indicating that causal and clinical interpretations should remain cautious given the modest effect sizes and limited variance captured by current GWAS resources.

关键词
ADHD GWAS Mendelian randomization genetic correlation reading‐ and language‐related skills
文献信息
期刊
JCPP advances
期刊简称
JCPP Adv
ISSN
2692-9384
发表日期
2026-07-18
语言
英语
国家/地区
United States
NLM ID
9918250414706676
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