Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample

Area of Science:

• Genomics
• Genetic Medicine

Background:

• Copy number variants (CNVs) are crucial in genomic medicine but lack systematic assessment for complex traits.
• Large rare CNVs are linked to schizophrenia (SCZ) and autism, but their population frequencies and pleiotropic effects are not fully understood.
• Exome-focused arrays, designed for sequence variation, are increasingly used in large cohorts, presenting an opportunity for CNV detection.

Purpose of the Study:

• To evaluate the capability of exome arrays (Illumina Human Exome Bead Chip) for detecting gene-focused CNVs.
• To assess the sensitivity and specificity of exome arrays for CNV detection compared to standard genome-wide association study (GWAS) arrays.
• To explore the utility of exome arrays for large-scale CNV analysis across diverse diseases.

Main Methods:

• Genotyping of 9100 Swedish subjects (3962 SCZ cases, 5138 controls) using both GWAS and exome arrays.
• Analysis of hybridization intensity data from exome arrays for CNV detection.
• Comparison of CNV detection results between exome and GWAS arrays.

Main Results:

• Exome arrays demonstrated high sensitivity and specificity for detecting genic CNVs (≥400 kb), including known pathogenic variants.
• The study replicated the finding of increased genic CNV enrichment in SCZ cases.
• Confirmed SCZ associations with 16p11.2 duplications and 22q11.2 deletions, and suggested a novel association with 11q12.2 deletions.

Conclusions:

• Exome-focused arrays are valuable tools for surveying large genic CNVs in extensive sample sizes.
• This approach facilitates well-powered CNV assessments and cross-disease comparisons, minimizing confounding factors.
• The findings open new avenues for understanding the role of CNVs in complex traits and diseases.