Fahey Laura, Lopez Lorna M
Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
Genes Brain Behav. 2024 Dec;23(6):e70011. doi: 10.1111/gbb.70011.
Genetic correlations have been reported between chronotype and both autism (AUT) and schizophrenia (SCZ), as well as between insomnia and attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BP), schizophrenia (SCZ) and major depression (MDD). Our study aimed to investigate these shared genetic variations using genome-wide and pathway-based polygenic score analyses. We computed polygenic scores using summary statistics from genome-wide association studies (GWAS) of ADHD (N = 225,534), AUT (N = 46,350), BP (N = 353,899), MDD (N = 500,199) and SCZ (N = 160,779). We tested their performance in predicting chronotype (N = 409,630) and insomnia (N = 239,918) status of UK Biobank participants. For pathway-based polygenic scores, we restricted genetic variation to SNPs that mapped to genes within 1377 Reactome pathways. Genome-wide polygenic scores for AUT, BP, MDD and SCZ were associated with an evening chronotype (p < 2.2 × 10, p = 4.8 × 10, p = 8.07 × 10 and p < 2.2 × 10, respectively). Polygenic scores for ADHD, AUT, BP, MDD SCZ were associated with insomnia (p < 2.2 × 10, p = 2.93 × 10, p = 2.9 × 10, p < 2.2 × 10 and p = 8.86 × 10, respectively). While pathway-based polygenic score analysis identified the KEAP1-NRF2 (p = 1.29 × 10) and mRNA Splicing-Minor Pathways (p = 1.52 × 10) as enriched for genetic variation overlapping between chronotype and BP, the majority of tested pathways yielded null findings, suggesting that specific shared genetic mechanisms between sleep-related phenotypes and neurodevelopmental/psychiatric conditions (NDPC) may be limited to a subset of pathways. Colocalisation analysis identified BP-associated SNPs in CUL3 and SF3B1 as being linked to changes in their expression. Our results strengthen evidence for shared genetic variation between NDPC and sleep-related phenotypes. We identify the KEAP1-NRF2 and mRNA Splicing-Minor Pathways as potentially mediating the disrupted circadian rhythm phenotype of BP.
已有研究报道了生物钟类型与自闭症（AUT）和精神分裂症（SCZ）之间的遗传相关性，以及失眠与注意力缺陷多动障碍（ADHD）、双相情感障碍（BP）、精神分裂症（SCZ）和重度抑郁症（MDD）之间的遗传相关性。我们的研究旨在通过全基因组和基于通路的多基因评分分析来探究这些共享的遗传变异。我们使用来自ADHD（N = 225,534）、AUT（N = 46,350）、BP（N = 353,899）、MDD（N = 500,199）和SCZ（N = 160,779）全基因组关联研究（GWAS）的汇总统计数据计算多基因评分。我们测试了它们在预测英国生物银行参与者的生物钟类型（N = 409,630）和失眠（N = 239,918）状态方面的表现。对于基于通路的多基因评分，我们将遗传变异限制在映射到1377个Reactome通路内基因的单核苷酸多态性（SNP）上。AUT、BP、MDD和SCZ的全基因组多基因评分与晚型生物钟类型相关（分别为p < 2.2×10、p = 4.8×10、p = 8.07×10和p < 2.2×10）。ADHD、AUT、BP、MDD、SCZ的多基因评分与失眠相关（分别为p < 2.2×10、p = 2.93×10、p = 2.9×10、p < 2.2×10和p = 8.86×10）。虽然基于通路的多基因评分分析确定KEAP1 - NRF2（p = 1.29×10）和mRNA剪接 - 次要通路（p = 1.52×10）在生物钟类型和BP之间的遗传变异中富集，但大多数测试通路得出了阴性结果，这表明睡眠相关表型与神经发育/精神疾病（NDPC）之间特定的共享遗传机制可能仅限于一部分通路。共定位分析确定CUL3和SF3B1中与BP相关的SNP与它们的表达变化有关。我们的结果加强了NDPC与睡眠相关表型之间共享遗传变异的证据。我们确定KEAP1 - NRF2和mRNA剪接 - 次要通路可能介导了BP的昼夜节律紊乱表型。
