medRxiv : the preprint server for health sciences · 2025
Genome-wide investigation highlights global and local pleiotropy linking neurodevelopmental disorders to acquired hearing problems.
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Zhang Qishu, Cabrera-Mendoza Brenda, Chen Qianyu, Davtian David, Qiu Dan, He Jun, Polimanti Renato
Аннотация
BACKGROUND: Neurodevelopmental disorders have been associated with hearing problems (HP) later in life, but there is limited information regarding their shared biology.
METHODS: We leveraged large-scale genome-wide datasets to estimate genetic correlation (global and local), polygenic overlap, and locus-specific pleiotropy among HP, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette syndrome (TS). Then, we investigated shared molecular functions, biological processes, and cellular components, and performed a drug-repurposing analysis to identify compounds that may target the pathogenic processes linking neurodevelopmental disorders to HP.
RESULTS: We observed high genetic correlation of HP with ASD (rg=0.72) and TS (rg=0.69). While HP-ADHD genetic correlation was low (rg=0.07), 40% of the causal variants were shared between these conditions, with only 53% of them showing concordant effect directions. We also identified nine chromosomal regions with evidence of ADHD-HP local genetic correlations with pleiotropic effects on other outcomes such as smoking initiation, brain-imaging phenotypes, and bilirubin levels. With respect to HP-ASD, we observed an inverse local genetic correlation within CD33 chromosomal region. Pleiotropy among HP, ASD, and ADHD was also identified in two variants (rs325485 and rs2207286) included within 95% credible sets related to neuropsychiatric conditions, altered hearing function, and other traits such as risk taking and insomnia. Drug-repurposing analyses identified anisomycin for HP-ASD shared biological mechanisms and five compounds related to HP-ADHD pleiotropy.
CONCLUSIONS: Our findings provide evidence that the comorbidity between neurodevelopmental disorders and HP is at least partially due to shared pathogenic processes acting through intrinsic and extrinsic factors.
METHODS: We leveraged large-scale genome-wide datasets to estimate genetic correlation (global and local), polygenic overlap, and locus-specific pleiotropy among HP, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette syndrome (TS). Then, we investigated shared molecular functions, biological processes, and cellular components, and performed a drug-repurposing analysis to identify compounds that may target the pathogenic processes linking neurodevelopmental disorders to HP.
RESULTS: We observed high genetic correlation of HP with ASD (rg=0.72) and TS (rg=0.69). While HP-ADHD genetic correlation was low (rg=0.07), 40% of the causal variants were shared between these conditions, with only 53% of them showing concordant effect directions. We also identified nine chromosomal regions with evidence of ADHD-HP local genetic correlations with pleiotropic effects on other outcomes such as smoking initiation, brain-imaging phenotypes, and bilirubin levels. With respect to HP-ASD, we observed an inverse local genetic correlation within CD33 chromosomal region. Pleiotropy among HP, ASD, and ADHD was also identified in two variants (rs325485 and rs2207286) included within 95% credible sets related to neuropsychiatric conditions, altered hearing function, and other traits such as risk taking and insomnia. Drug-repurposing analyses identified anisomycin for HP-ASD shared biological mechanisms and five compounds related to HP-ADHD pleiotropy.
CONCLUSIONS: Our findings provide evidence that the comorbidity between neurodevelopmental disorders and HP is at least partially due to shared pathogenic processes acting through intrinsic and extrinsic factors.