Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Human Genetics

Background:

• Bipolar disorder (BD) genetic risk involves common alleles, but rare copy number variants (CNVs) role is unclear.
• BD subtypes (SAB, BD I, BD II) vary in psychosis, mania, and depression; their genetic underpinnings are poorly understood.

Purpose of the Study:

• To investigate the role of rare large CNVs in the genetic risk of BD and its subtypes.
• To compare the contributions of rare CNVs and common variants (via schizophrenia polygenic risk score) to BD and psychosis risk.

Main Methods:

• Analyzed rare large CNVs in 6353 BD cases (including subtypes) and 8656 controls.
• Calculated CNV burden and polygenic risk scores (PRS) for schizophrenia.
• Evaluated relative contributions of rare and common variants to BD, BD subtypes, and psychosis.

Main Results:

• CNV burden did not differ between overall BD and controls.
• SAB showed significantly increased CNV burden compared to controls, BD I, and BD II.
• SAB had higher CNV burden and schizophrenia PRS than BD I (with and without psychosis).
• Within BD I, psychosis was linked to higher schizophrenia PRS, but not CNV burden.

Conclusions:

• CNV burden in bipolar disorder is specifically associated with schizoaffective disorder bipolar type (SAB).
• Rare and common genetic variants may differentially contribute to the risk of psychosis and other psychiatric symptoms.