Dataset Information

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

ABSTRACT: 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. Subtypes of BD including 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 genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS:Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS:CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not 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.

SUBMITTER: Charney AW

PROVIDER: S-EPMC6586545 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Charney Alexander W AW Stahl Eli A EA Green Elaine K EK Chen Chia-Yen CY Moran Jennifer L JL Chambert Kimberly K Belliveau Richard A RA Forty Liz L Gordon-Smith Katherine K Lee Phil H PH Bromet Evelyn J EJ Buckley Peter F PF Escamilla Michael A MA Fanous Ayman H AH Fochtmann Laura J LJ Lehrer Douglas S DS Malaspina Dolores D Marder Stephen R SR Morley Christopher P CP Nicolini Humberto H Perkins Diana O DO Rakofsky Jeffrey J JJ Rapaport Mark H MH Medeiros Helena H Sobell Janet L JL Backlund Lena L Bergen Sarah E SE Juréus Anders A Schalling Martin M Lichtenstein Paul P Knowles James A JA Burdick Katherine E KE Jones Ian I Jones Lisa A LA Hultman Christina M CM Perlis Roy R Purcell Shaun M SM McCarroll Steven A SA Pato Carlos N CN Pato Michele T MT Di Florio Ariana A Craddock Nick N Landén Mikael M Smoller Jordan W JW Ruderfer Douglas M DM Sklar Pamela P

Biological psychiatry 20181220 2

<h4>Background</h4>Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including 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 genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.<h4>Methods</h4> ...[more]

PMID: 30686506

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Project description:Endometriosis is a complex gynecological condition that affects 6-10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3 × 10(-4); a deletion at SGCZ on 8p22 (P = 7.3 × 10(-4), OR = 8.5, Cl = 2.3-31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6 × 10(-4), OR = 14.1, Cl = 2.7-90.9), and a deletion at 11q14.1 (P = 5.7 × 10(-4), OR = 33.8, Cl = 3.3-1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.

Dataset Information

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

Publications

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

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