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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Study Report

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Basic Info

Reference	Schumacher, J.,2005 PMID: 16380920
Citation	Schumacher, J., R. Kaneva, et al. (2005). "Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24." Am J Hum Genet 77(6): 1102-1111.
Disease Type	Bipolar Disorder
Study Design	pedigree
Study Type	Genome-wide linkage study
Sample Size	52 families (448 genotyped individuals) for genomewide scan;108 families (728 genotyped individuals) for fine-mapping linkage analysis
SNP/Region/Marker Size	435 STRs for whole genome wide
Predominant Ethnicity	Caucasian
Population	Spanish, Romany, Bulgarian and German

Detail Info

Sample Diagnosis	DSM
Sample Status	The genome scan was performed on 52 families consisting of 448 subjects, of whom 260 were affected (according to the broad phenotype definition, ASDIII [described below]). An additional sample of 56 German families with 280 members (117 affected) for which a previously completed genome scan produced overlapping results (Cichon et al. 2001) was included for the fine-mapping stage. The inclusion criteria for BPAD-affected families were the presence of (1) a proband with bipolar I disorder (BPI) and (2) a secondary affected sibling with either BPI, bipolar II (BPII), schizoaffective disorder bipolar type (SA/BP), or unipolar recurrent depression (UPR). All individuals were interviewed by an experienced psychiatrist. The Schedule for Affective Disorders and Schizophrenia- Lifetime Version (SADS-L) (Endicott and Spitzer 1978) was used for the German and Spanish families. The Schedules for Clinical Assessment in Neuropsychiatry (Wing et al. 1990) was used for the Bulgarian and Romany families. The affected status definitions (ASD) used in the linkage analysis were as follows: ASDI (narrow) includes individuals with BPI only, with all other psychiatric diagnoses coded as 'unknown'; ASDII (medium) includes all individuals who received a diagnosis of BPI, BPII, or SA/BP; and ASDIII (broad) also includes individuals with UPR.
Technique	genotyping
Statistical Method	Nonparametric linkage (NPL) analysis of the genome scan data was performed using the current version of GENEHUNTER, version 2.1 release 5 (Kruglyak et al.1996; Kruglyak and Lander 1998; Markianos et al.2001). Marker-allele frequencies were estimated for all samples by a maximum-likelihood procedure with use of the program MENDEL (version 5.5). Identical-bydescent allele sharing among all affected family members was calculated for the narrow, medium, and broad affection-status definition with use of the GENEHUNTER score function S-ALL.
Result Summary	The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.

Regions reported by this study for BD (count: 5)

Region	Statistical Values	Author Comments	Result Category
6q16	Linkage Analysis: ASDII(including BPI, BPII, or SA/BP) NPL = 1.42, P-value = 0.358; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 1.24, P-value = 0.468; for German subsample, ASDI(only including BPI) NPL = 2.42, P-value = 0.058; ASDII(including BPI, BPII, or SA/BP) NPL = 2.55, P-value = 0.052; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 2.15, P-value = 0.104	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
6q23	Linkage Analysis: for Fine-mapping sample, ASDI(only including BPI) NPL = 1.75, P-value = 0.246; ASDII(including BPI, BPII, or SA/BP) NPL = 2.85, P-value = 0.022; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 2.59, P-value = 0.054; for Bulgarian subsample, ASDI(only including BPI) NPL = 2.69, P-value = 0.026; ASDII(including BPI, BPII, or SA/BP) NPL = 2.69, P-value = 0.026; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 2.42, P-value = 0.044; ASDII(including BPI, BPII, or SA/BP) NPL = 2.08, P-value = 0.15	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
6q24	Linkage Analysis: for Fine-mapping sample, ASDI(only including BPI) NPL = 2.27, P-value = 0.096; ASDII(including BPI, BPII, or SA/BP) NPL = 3.18, P-value = 0.008; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 2.53, P-value = 0.06; for Romany subsample: peak I, ASDI(only including BPI) NPL = 2.99, P-value = 0.058; ASDII(including BPI, BPII, or SA/BP) NPL = 3.21, P-value = 0.04; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 3.46, P-value = 0.071; for Romany subsample: peak II, ASDI(only including BPI) NPL = 2.52, P-value = 0.096; ASDII(including BPI, BPII, or SA/BP) NPL = 2.69, P-value = 0.062; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 4.87, P-value = 0.044; for German subsample, ASDI(only including BPI) NPL = 1.23, P-value = 0.47; ASDII(including BPI, BPII, or SA/BP) NPL = 1.76, P-value = 0.23; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = â€¦, P-value = ; for Bulgarian subsample, ASDI(only including BPI) NPL = 1.43, P-value = 0.43; ASDII(including BPI, BPII, or SA/BP) NPL = 1.43, P-value = 0.444; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 1.85, P-value = 0.044	Significant linkage was found in this region. Significant linkage was found in this region.	Positive
1p35-p36	Linkage Analysis: for Fine-mapping sample, ASDI(only including BPI) NPL = 1.93, P-value = 0.128; ASDII(including BPI, BPII, or SA/BP) NPL = 2.65, P-value = 0.02; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 3.69, P-value = 0.003; for Spanish subsample, ASDI(only including BPI) NPL = 1.44, P-value = 0.294; ASDII(including BPI, BPII, or SA/BP) NPL = 2.06, P-value = 0.116; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 3.97, P-value = 0.005; for Romany subsample, ASDI(only including BPI) NPL = 3.21, P-value = 0.034; ASDII(including BPI, BPII, or SA/BP) NPL = 2.7, P-value = 0.064; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 1.78, P-value = 0.184; for Bulgarian subsample, ASDI(only including BPI) NPL = 1.26, P-value = 0.418; ASDII(including BPI, BPII, or SA/BP) NPL = 1.26, P-value = 0.416	Significant linkage was found in this region. Significant linkage was found in this region.	Positive
4q31	Linkage Analysis: for Fine-mapping sample, ASDI(only including BPI) NPL = 2.85, P-value = 0.01; ASDII(including BPI, BPII, or SA/BP) NPL = 3.18, P-value = 0.004; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 2.36, P-value = 0.016; for Romany subsample, ASDI(only including BPI) NPL = 3.52, P-value = 0.014; ASDII(including BPI, BPII, or SA/BP) NPL = 3.34, P-value = 0.016; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 5.49, P-value = 0.015; for German subsample, ASDI(only including BPI) NPL = 2.15, P-value = 0.038; ASDII(including BPI, BPII, or SA/BP) NPL = 2.58, P-value = 0.012; ASDIII(including BPI, BPII, SA/BP, or UPR) NPL = 1.61, P-value = 0.244; for Bulgarian subsample, ASDI(only including BPI) NPL = 1.29, P-value = 0.258; ASDII(including BPI, BPII, or SA/BP) NPL = 1.28, P-value = 0.244	Significant linkage was found in this region. Significant linkage was found in this region.	Positive