Copy number variation in bipolar disorder.

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Large copy number variants (CNVs) are established schizophrenia (SZ) risk factors.
• The role of CNVs in bipolar disorder (BD) remains less understood.
• Previous studies indicate a potential genetic overlap between SZ and BD.

Purpose of the Study:

• To investigate the occurrence and impact of CNVs in a large UK bipolar disorder sample.
• To compare CNV frequencies in BD with existing SZ and control cohorts.
• To identify specific CNV loci and gene regions associated with BD risk.

Main Methods:

• Analysis of CNVs in 2591 UK BD patients.
• Meta-analysis combining new BD data with 6882 SZ and 8842 control subjects.
• Statistical testing for association of CNV loci with BD and SZ, including multiple-testing correction.

Main Results:

• Three SZ-associated CNV loci showed evidence of contributing to BD risk: 1q21.1 duplications, 3q29 deletions, and 16p11.2 duplications.
• 16p11.2 duplications survived multiple-testing correction.
• Rare exonic CNVs were enriched in BD cases across 20 gene regions, but did not survive correction.
• Very large CNVs (>500 kb), especially deletions >1 Mb, were significantly less common in BD than SZ.

Conclusions:

• Specific CNV loci, previously linked to SZ, also confer risk for BD.
• The genetic architecture of BD involves large CNVs, but to a lesser extent than SZ.
• 16p11.2 duplications represent a significant recurrent CNV risk factor for BD.