Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases
By
Alexander Charney,
Eli A Stahl,
Elaine K Green,
Chia-Yen Chen,
Jennifer L. Moran,
Kimberly Chambert,
Richard A Belliveau,
Liz Forty,
Katherine Gordon-Smith,
Phil H Lee,
Evelyn J Bromet,
Peter F Buckley,
Michael A Escamilla,
Ayman H. Fanous,
Laura J Fochtmann,
Douglas S Lehrer,
Dolores Malaspina,
Stephen R Marder,
Christopher P Morley,
Humberto Nicolini,
Diana O Perkins,
Jeffrey J Rakofsky,
Mark H Rapaport,
Helena Medeiros,
Janet L Sobell,
Lena Backlund,
Sarah E Bergen,
Anders Juréus,
Martin Schalling,
Paul Lichtenstein,
James A Knowles,
Katherine E. Burdick,
Ian Jones,
Lisa A Jones,
Christina M Hultman,
Roy Perlis,
Shaun M. Purcell,
Steven A McCarroll,
Carlos N. Pato,
Michele T Pato,
Ariana Di Florio,
Nick Craddock,
Mikael Landén,
Jordan W Smoller,
Douglas M. Ruderfer,
Pamela Sklar
Posted 03 Sep 2018
bioRxiv DOI: 10.1101/406215
(published DOI: 10.1016/j.biopsych.2018.12.009)
Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood. Methods: Rare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk. Results: CNV burden did not differ in BD relative to controls when treated as a single diagnostic entity. Burden in SAB was increased compared to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were higher in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 x 10-5). Within BD I, psychosis was associated with higher SCZ PRS (p-value = 0.005) but not with CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
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