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	Middleton, F. A.,2004 PMID: 15060841
Citation	Middleton, F. A., M. T. Pato, et al. (2004). "Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22." Am J Hum Genet 74(5): 886-897.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	pedigree
Study Type	Genome-wide linkage study
Sample Size	12 families
SNP/Region/Marker Size	11,560 SNPs , 10-cM microsatellite marker set and the more dense 4-cM marker set for whole genome wide
Predominant Ethnicity
Population	Portuguese

Detail Info

Sample Diagnosis	DSM
Sample Status	We used a total of 25 families for linkage analysis in the present study. These families were represented by pedigrees that included 233 individuals (83 founders, 150 nonfounders). The mean family size was 9.32 (range 4-17; mode 5), spanning a mean of 2.88 generations (range 2-4; mode 3). In these families, we ran a total of 148 HMA10K assays, with samples from 88 female and 60 male subjects. The mean number of assays per family was 5.9 (range 3-11; mode 8). Full definitive diagnoses were available for 140 of the 148 subjects, with the remainder of subjects analyzed using the 'unknown' phenotype. Of the affected subjects, 73 were diagnosed with bipolar disorder and 2 were diagnosed with schizoaffective- bipolar disorder, representing a mean of 3.0 affected subjects per family. Of the 25 families, 15 were from the Azores, 5 from Madeira, and 5 from the city of Coimbra on the Portuguese mainland. To compare the HMA10K assay with microsatellite assays, we performed linkage analysis using the same individuals in 12 of the 25 families. These 12 families had been used in a previous microsatellite study of bipolar disorder involving 16 families (Pato et al., in press) and represented all families with sufficient DNA available from that study. These 12 families included 107 subjects (36 founders, 71 nonfounders) with a mean family size of 8.92 (range 5-17; mode 7), spanning 2.75 generations (range 2-4; mode 3). A total of 68 subjects were used for the comparisons (29 males, 39 females). Definitive diagnoses were available for 66 of the subjects. A total of 35 subjects were diagnosed with bipolar or schizoaffective-bipolar disorder (mean 2.91 affected individuals per family). Of the 12 families, 8 were from the Azores, 1 was from Madeira, and 3 were from Coimbra.
Replication Size	25 families including 233 individuals (83 founders, 150 nonfounders)
Technique	genotyping(HMA10K and microsatellite assays)
Statistical Method	We used MERLIN (Multipoint Engine for Rapid Likelihood Inference) software (Abecasis et al. 2002) to analyze the compiled pedigree structures of the 25-family and 12-family data sets, to examine the information content of the HMA10K and microsatellite assays in these sets, and to perform multipoint NPL analysis.
Result Summary	In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays.The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.

Regions reported by this study for BD (count: 9)

Region	Statistical Values	Author Comments	Result Category
Chr 2_38Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 2.18, NPL(HMA10K) = 3.15 for 12 families; NPL(HMA10K) = 1.83 for 25 families.	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
Chr 2_145Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = -2.19, NPL(HMA10K) = 2.73 for 12 families; NPL(HMA10K) = 3.09 for 25 families.	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
Chr 6_104Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 1.96, NPL(4-cM Microsatellite Marker Assay) = 1.88, NPL(HMA10K) = 1.92 for 12 families; NPL(HMA10K) = 1.86 for 25 families.	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
Chr 20_60Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = ND, NPL(4-cM Microsatellite Marker Assay) = ND, NPL(HMA10K) = 2.36 for 12 families; NPL(HMA10K) = 2.99 for 25 families.	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
Chr 4_91Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 0.43, NPL(HMA10K) = 1.33 for 12 families; NPL(HMA10K) = 2.97 for 25 families.	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
Chr 2_57Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = -0.44, NPL(HMA10K) = 1.99 for 12 families; NPL(HMA10K) = 2.98 for 25 families.	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
11p11	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 2.62, NPL(4-cM Microsatellite Marker Assay) = 3.31, NPL(HMA10K) = 4.44 for 12 families; NPL(HMA10K) = 2.51 for 25 families.	Significant linkage was found in this region. Significant linkage was found in this region.	Positive
Chr 16_20Mb	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 2.27, NPL(4-cM Microsatellite Marker Assay) = ND, NPL(HMA10K) = 1.47 for 12 families; NPL(HMA10K) = 2.89 for 25 families.	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
6q22	Linkage analysis: NPL(10-cM Microsatellite Marker Assay) = 0.79, NPL(4-cM Microsatellite Marker Assay) = 1.16, NPL(HMA10K) = 3.87 for 12 families; NPL(HMA10K) = 4.2 for 25 families.	Significant linkage was found in this region. Significant linkage was found in this region.	Positive