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. 2025 Nov 20.
doi: 10.1097/YPG.0000000000000406. Online ahead of print.

Shared genetic architecture between autism spectrum disorder, loneliness, and social isolation reveals novel genetic loci

Sigrun Hope  1   2   3 , Aihua Lin  4 , Linn Rodevand  4 , Saira Jameela Hübenette  1 , Daniel S Quintana  1   4   5 , Ida E Sønderby  1   4   6 , Weiqiu Cheng  4 , Oleksandr Frei  4 , Shahram Bahrami  4 , Guy F L Hindley  4   7   8 , Anett Kaale  3   6 , Alexey A Shadrin  4 , Kevin S O'Connell  4 , Nadine Parker  4 , Srdjan Djurovic  4   6   9 , Terje Nærland  1   3 , Ole A Andreassen  1   4
Affiliations

Shared genetic architecture between autism spectrum disorder, loneliness, and social isolation reveals novel genetic loci

Sigrun Hope et al. Psychiatr Genet. .

Abstract

Objective: Deficits in social communication and social interaction are core features of autism spectrum disorder (ASD), and studies suggest that loneliness and social isolation are common. ASD has a strong genetic basis, but the genetic architecture and overlap with social phenotypes are not clear.

Methods: We analyzed summary statistics from genome-wide association studies on ASD (46 350), loneliness (452 302), and social isolation (288 950), using linkage disequilibrium score regression, local analysis of covariant annotation (LAVA), bivariate causal mixture model (MiXeR), and the conditional/conjunctional false discovery rate (cond/conjFDR).

Results: For ASD and social isolation, we found nonsignificant global genetic correlation (rg = 0.02, P = 0.8), but LAVA identified 72 genomic regions with bidirectional correlations, and MiXeR estimated that 8.7 k of 13.1 k variants (81%) were shared, of which 53% had concordant effect directions. For ASD and loneliness, we found a positive genetic correlation (rg = 0.26, P = 2e-10), LAVA identified 80 genomic regions with bidirectional genetic correlations, and MiXeR suggested that at least 3.8 k variants were shared. We identified nine specific shared genetic loci between ASD and loneliness and eight between ASD and social isolation (conjFDR < 0.05). Of these, 12 loci were novel for ASD. Genes mapped to these loci are involved in γ-aminobutyric acid (GABA), glutamate, calcium, and stress hormone signaling, cerebral glucose transport, TAU-accumulation, and immune function.

Conclusion: We found extensive overlap in genetic architecture between ASD, loneliness, and social isolation, with bidirectional effects. By leveraging data for ASD and social traits, we identified 12 novel ASD related genetic loci implicating several genes, thereby elucidating potential pathways underlying their shared genetic architecture.

Keywords: autism; genome-wide association study; loneliness; social isolation.

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