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<p>Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence (<i>P-value</i> = 1.88×10<sup><i>-13</i></sup>, <i>beta</i> = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C (<i>P-value</i> = 7.05×10<sup><i>-08</i></sup>, <i>beta</i> = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of <i>GCH1</i> transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T (<i>P-value</i> = 8.17×10<sup><i>-08</i></sup>, <i>beta</i> = 0.30), colocalised with <i>GCH1</i> splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating <i>GCH1</i> expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.</p>

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Genetic co-regulation of neopterin and Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Valeria Orrù,
  • Michele Marongiu,
  • Maristella Steri,
  • Mara Marongiu,
  • Carlo Sidore,
  • Valentina Serra,
  • Mauro Pala,
  • Stefania Olla,
  • Noemi Toggia,
  • Matteo Floris,
  • Monia Lobina,
  • Maria Grazia Piras,
  • Antonella Mulas,
  • Andrea Maschio,
  • Mariano Dei,
  • Marina Parolini,
  • Cinzia Dellanoce,
  • Alessandro Delitala,
  • Stella Aslibekyan,
  • Adam Auton,
  • Robert K. Bell,
  • Katelyn Kukar Bond,
  • Zayn Cochinwala,
  • Sayantan Das,
  • Kahsaia de Brito,
  • Emily DelloRusso,
  • Chris Eijsbouts,
  • Sarah L. Elson,
  • Chris German,
  • Julie M. Granka,
  • Barry Hicks,
  • David A. Hinds,
  • Reza Jabal,
  • Aly Khan,
  • Matthew J. Kmiecik,
  • Alan Kwong,
  • Yanyu Liang,
  • Keng-Han Lin,
  • Matthew H. McIntyre,
  • Shubham Saini,
  • Anjali J. Shastri,
  • Jingchunzi Shi,
  • Suyash Shringarpure,
  • Qiaojuan Jane Su,
  • Vinh Tran,
  • Joyce Y. Tung,
  • Catherine H. Weldon,
  • Wanwan Xu,
  • David Schlessinger,
  • Jonica Campolo,
  • Marcella Devoto,
  • Magdalena Zoledziewska,
  • Francesco Cucca,
  • Edoardo Fiorillo

摘要

Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence (P-value = 1.88×10-13, beta = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C (P-value = 7.05×10-08, beta = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of GCH1 transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T (P-value = 8.17×10-08, beta = 0.30), colocalised with GCH1 splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating GCH1 expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.