Shared Genetic Links Between Sleep, Neurodevelopmental and Neuropsychiatric Conditions: A Genome-Wide and Pathway-Based Polygenic Score Analysis

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 × 10⁻¹⁶, p = 4.8 × 10⁻³, p = 8.07 × 10⁻⁴ and p < 2.2 × 10⁻¹⁶, respectively). Polygenic scores for ADHD, AUT, BP, MDD SCZ were associated with insomnia (p < 2.2 × 10⁻¹⁶, p = 2.93 × 10⁻³, p = 2.9 × 10⁻⁷, p < 2.2 × 10⁻¹⁶ and p = 8.86 × 10⁻³, respectively). While pathway-based polygenic score analysis identified the KEAP1-NRF2 (p = 1.29 × 10⁻⁸) and mRNA Splicing-Minor Pathways (p = 1.52 × 10⁻⁸) 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.