BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

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Basic Info

Reference	Georgieva, L., 2014 PMID: 25055870
Citation	Georgieva, L., et al. (2014). "De novo CNVs in bipolar affective disorder and schizophrenia." Hum Mol Genet.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	family-based and case-control
Study Type	Genome-wide CNV study
Sample Size	449 probands: 368 with BD (256 from Bulgaria and 112 from the UK) and 76 with SZ (15 from Bulgaria and 61 from the UK).
SNP/Region/Marker Size	21 de novo CNVs
Predominant Ethnicity	Caucasian
Population	Bulgaria and UK

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Three hundred and eighty-one probands were from parent-offspring trios (342 with BD and 39 with SZ), 42 were fromfamilies with 2 affected siblings (16 with BD and 26 with SZ) and 21 (10 BD and 11 SZ) were from families with more complex structures, including families with a mixture of diagnoses. Probands affected with schizoaffective disorder were excluded from this study. Probands with a history of psychosis in a sibling or parent (50 with BD and 37 with SZ) were included, as none of the risk CNVs identified to date is sufficiently penetrant to fully explain the disorder in carriers, and therefore, we wanted to test whether familial cases can also have de novo CNVs. The proportion of affected sibling pairs with SZ from the UK is very high because part of this cohort was recruited as affected sib-pairs for linkage analysis, whereas all BD trios were recruited specifically for studying parent-offspring trios. Each proband had a history of hospitalisation and was interviewed with an abbreviated version of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Consensus best-estimate diagnoses were made according to DSM-IV criteria by two researchers.
Technique	Genotyping of blood-derived DNA from all samples was performed at the Stanley Centre for Psychiatric Research at the Broad Institute of MIT, USA on two arrays: HumanOmni Express-12v1 (referred further for short as 'OmniExpress array'), containing 730525 probes, and any poorly performing samples were re-genotyped on HumanOmniExpressExome-8v1 ('Combo array'), containing 951117 probes.
Statistical Method	Raw intensity data were processed using Illumina Genome Studio software (v2011.1). SNPs were clustered using the current samples, and LRR and B-allele frequencies were generated for CNV detection. PennCNV was used to call CNVs following the standard protocol and adjusting for GC content. Sample-level QC was performed using the QC metrics generated by PennCNV. All individual CNVs also went through QC filtering. First, raw CNVs in the same sample were joined together if the distance separating them was <50% of their combined length. CNVs were then excluded if they were either <10 kb, covered by <10 probes, overlapped with low copy repeats by >50% of their length (using PLINK) or had a probe density of >20 kb per probe. The remaining CNVs from each dataset were then analysed together and CNV loci with a frequency of >1% were excluded using PLINK. The putative de novo CNVs were validated with the median z-score outlier method. The z-score histograms of CNVs with marginal z-scores were manually inspected. For all putative de novo CNVs, the LRR and B-allele frequencies were also visually inspected using Illumina Genome Studiov2011.1 software. Validation of all remaining putative de novo CNVs was performed using real-time PCR based on SYBR-Green I fluorescence with at least three primer sets per CNV. All samples were amplified using Sensimix kit (Bioline, UK), and data were analysed using Rotor-Gene Q series software. Each primer set was compared with a primer set outside the CNV which served as â€˜controlâ€™ and data were normalized using delta Ct (cycle threshold) values.
Result Summary	We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size ofde novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs.

CNVs reported by this study for BD (count: 15)

Name	Position	Type	Author Comments
CNV_Lyudmila Georgieva[2014]_1	chr2:175365518-175813657	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_2	chr5:92414916-95724985	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_3	chr6:23671880-23724469	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_4	chr9:23765046-23953634	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_5	chr10:6968905-6985007	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_6	chr10:56517409-56677171	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_15	chr22:21069073-21608479	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_14	chr20:14771194-14853050	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_13	chr19:30861683-36685690	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_12	chr18:28277082-28375949	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_11	chr17:57696973-57779678	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_10	chr16:29595483-30198151	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_9	chr16:28825605-29043450	duplication	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_8	chr16:6891681-6922307	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)
CNV_Lyudmila Georgieva[2014]_7	chr11:84139937-84345829	deletion	15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb) 15 de novo CNVs were found in BD probands, a rate of 4.1% (2.4% for CNVs >100 kb)

Genes reported by this study for BD (count: 10)

Gene	Statistical Values/Author Comments	Result Category
CLTC	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
CHRNA1	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
ELAVL2	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
DLG2	The more likely candidate loci is in this gene. The more likely candidate loci is in this gene.	Trend
PCDH15	The loci in this gene impacted by de novo CNVs have been previously implicated in neuropsychiatric d...... The loci in this gene impacted by de novo CNVs have been previously implicated in neuropsychiatric disorders, which enhance their credibility as candidates for BD. More...	Trend
MACROD2	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
RBFOX1	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
WIPF1	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
PTRH2	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend
CHN1	A de novo CNV in this gene was detected in BD. A de novo CNV in this gene was detected in BD.	Trend