m⁶A Modification Genetic Variants Associated with Autism Spectrum Disorder Risks.

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder with high heritability.
• The role of N6-methyladenosine (m6A) epigenetic modifications in ASD pathogenesis is largely unknown.
• Understanding these mechanisms is crucial for developing targeted interventions.

Purpose of the Study:

• To identify m6A-QTL single nucleotide polymorphisms (SNPs) and modification genes associated with ASD.
• To investigate the functional implications of these genetic variants in neurodevelopmental pathways.
• To provide insights into the epigenetic underpinnings of ASD.

Main Methods:

• Bioinformatics analysis of m6A-QTL data and ASD genetic databases.
• Two-stage population validation in Chinese and European cohorts (totaling over 20,000 individuals).
• Functional annotation of candidate variants and target genes, including transcription factor binding analysis.

Main Results:

• Identified 2830 SNPs associated with m6A modification levels.
• Discovered 91 m6A-QTL-associated ASD candidate SNPs in the Chinese cohort.
• Validated 8 variants in the European cohort, with three high-confidence variants (rs10242048, rs2304447, rs4074309).
• rs4074309 potentially regulates STAT6 m6A levels and LRP1 expression, involving THAP1 binding and neurodevelopmental pathways (JAK-STAT, tau-protein kinase).

Conclusions:

• Genetic variants in m6A modification genes contribute to ASD susceptibility.
• m6A modification plays a significant role in neurodevelopmental disorders.
• The study provides novel insights into the epigenetic mechanisms underlying ASD.