Structure of a polymorphic repeat at the CACNA1C schizophrenia locus.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Genetic variations in the CACNA1C gene's intron 3 are linked to neuropsychiatric disorders like schizophrenia.
• Analyzing causal variants is challenging due to a nearby variable-number tandem repeat (VNTR).

Purpose of the Study:

• To investigate the structural diversity and population variability of the CACNA1C intron 3 VNTR.
• To understand the relationship between VNTR alleles, gene expression, and neuropsychiatric disease risk.

Main Methods:

• Utilized 155 long-read genome assemblies from 78 diverse individuals.
• Clustered VNTR sequences into 7 structural alleles (Types) based on repeat unit differences.
• Analyzed linkage disequilibrium with genome-wide association study (GWAS) variants and assessed gene expression.

Main Results:

• Identified 7 structural VNTR alleles (Types), with some related by duplication and others showing early divergence.
• Discovered rare, diverged VNTR Types primarily in individuals of African ancestry.
• Established complete linkage disequilibrium between a risk haplotype and schizophrenia GWAS variants, associated with reduced CACNA1C brain expression.

Conclusions:

• Sequence variation within the human-specific CACNA1C intron 3 VNTR influences gene expression.
• Characterized novel VNTR alleles at a key locus for neuropsychiatric GWAS.
• The VNTR polymorphism predates early hominin emergence and impacts gene regulation relevant to brain function.