European archives of psychiatry and clinical neuroscience · 2026
Shared genetic architecture across social disconnection, social disadvantage, and psychiatric and neurodevelopmental traits.
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Feng Yanchen, Li Qiufang, Sun Lu, Dang Xue, Guo Ziyi, Yao Jianping, Li Jinyao, Song Jiabin, Zhao Min, Liu Feixiang
Аннотация
BACKGROUND: Reduced social connectedness and impaired social functioning are observed across diverse social, psychiatric, and neurodevelopmental phenotypes, but their underlying multivariate genetic architecture remains unclear.
METHODS: We integrated GWAS summary statistics for Feeling lonely, social deprivation, major depressive disorder, generalized anxiety disorder, and autism spectrum disorder using Genomic SEM to characterize their shared genetic structure. A common-factor GWAS was subsequently performed to identify variants associated with the shared genetic component. Genome-wide significant signals were further characterized using functional annotation, gene-based analysis, statistical fine-mapping, sCCA-TWAS and FOCUS, together with gene-set, tissue and cell-type enrichment and partitioned heritability analyses.
RESULTS: The five phenotypes were captured by a common genetic factor with acceptable approximate fit (CFI = 0.963, SRMR = 0.072), with the strongest loadings observed for MDD, Feeling lonely, and GAD. The common-factor GWAS identified 40 genome-wide significant loci, including 25 that reached genome-wide significance only in the multivariate analysis relative to the constituent GWASs. Fine-mapping prioritized six variants with high posterior support across the SORCS3, TENM2, SOX5, and MDGA2 regions, including two SORCS3 variants supported by both SuSiE and FINEMAP. sCCA-TWAS identified 81 Bonferroni-significant expression-feature associations, and FOCUS prioritized 11 genes, seven of which were also significant in sCCA-TWAS. Functional analyses converged on neurodevelopment, synaptic organization, GABAergic and glutamatergic processes, brain tissues, fetal-brain chromatin, and evolutionarily conserved and regulatory genomic regions.
CONCLUSION: These findings identify a shared genetic dimension relevant to social connectedness and functioning across social, psychiatric, and neurodevelopmental phenotypes. Its polygenic architecture converges on neural developmental, synaptic, and regulatory genomic processes.
METHODS: We integrated GWAS summary statistics for Feeling lonely, social deprivation, major depressive disorder, generalized anxiety disorder, and autism spectrum disorder using Genomic SEM to characterize their shared genetic structure. A common-factor GWAS was subsequently performed to identify variants associated with the shared genetic component. Genome-wide significant signals were further characterized using functional annotation, gene-based analysis, statistical fine-mapping, sCCA-TWAS and FOCUS, together with gene-set, tissue and cell-type enrichment and partitioned heritability analyses.
RESULTS: The five phenotypes were captured by a common genetic factor with acceptable approximate fit (CFI = 0.963, SRMR = 0.072), with the strongest loadings observed for MDD, Feeling lonely, and GAD. The common-factor GWAS identified 40 genome-wide significant loci, including 25 that reached genome-wide significance only in the multivariate analysis relative to the constituent GWASs. Fine-mapping prioritized six variants with high posterior support across the SORCS3, TENM2, SOX5, and MDGA2 regions, including two SORCS3 variants supported by both SuSiE and FINEMAP. sCCA-TWAS identified 81 Bonferroni-significant expression-feature associations, and FOCUS prioritized 11 genes, seven of which were also significant in sCCA-TWAS. Functional analyses converged on neurodevelopment, synaptic organization, GABAergic and glutamatergic processes, brain tissues, fetal-brain chromatin, and evolutionarily conserved and regulatory genomic regions.
CONCLUSION: These findings identify a shared genetic dimension relevant to social connectedness and functioning across social, psychiatric, and neurodevelopmental phenotypes. Its polygenic architecture converges on neural developmental, synaptic, and regulatory genomic processes.