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	Xu, H.,2010 PMID: 21165893
Citation	Xu, H., R. Cheng, et al. (2010). "Fine mapping of candidate regions for bipolar disorder provides strong evidence for susceptibility loci on chromosomes 7q." Am J Med Genet B Neuropsychiatr Genet.
Disease Type	Bipolar Disorder
Study Design	pedigree and family-based
Study Type	Candidate-region linkage study and candidate-gene association study
Sample Size	BP pedigree sample (865 individuals from 56 pedigrees)
SNP/Region/Marker Size	73 microsatellite markers for 10 regions
Predominant Ethnicity	Caucasian
Population	American and Israeli
Age Group	Adults

Detail Info

Sample Diagnosis	RDC
Sample Status	The present sample consists of 865 individuals (Caucasian, age 16 or over) from 56 extended pedigrees with a high density of BP. All the subjects are Caucasian. Twenty-nine of the 40 core pedigrees, as well as the 16 new families, were collected in the US and are of European ancestry; the remaining 11 families (core sample) were collected in Israel and are of Middle-Eastern extraction. To determine affection status, we used the research diagnostic criteria (RDC) [Spitzer et al., 1978]. Best-estimate consensus diagnoses were based on direct clinical interviews using the lifetime version of the schedule for affective disorders and schizophrenia (SADSLA) [Endicott and Spitzer, 1978] modified for BP, supplemented by family history and medical records. We used three standard diagnostic models for affection status: BP1 (manic syndromes, mostly bipolar I disorder), BP2 (BP1 plus bipolar II disorder with major depression) and BP3 (BP2 plus recurrent major depressive disorders). Individuals considered unaffected under any of these models (mainly never mentally ill) were coded as unknown in the statistical analyses.As mentioned, our previous study [Liu et al., 2003] was based on a subset of the present sample (373 individuals from 40 families), which gleaned the bulk of genetic information, while minimizing genotyping cost.
Technique	PCR and sequencing
Statistical Method	For linkage study:Two-point and multipoint parametric analyses were performed using the MLINK and LINKMAP programs (FASTLINK package),respectively [Cottingham et al., 1993].Multipoint affected sib-pair (ASP) analysis was conducted using Genehunter version 2.0 [Kruglyak et al., 1996].For association study:FBAT (http://www.biostat.harvard.edu/ fbat/fbat.htm) was used to test for family based association between BP and individual markers.
Result Summary	We obtained experiment-wide significant linkage on chromosome 7q34 (LOD score 3.53, P < 0.001), substantially stronger than that observed in the genome-wide scan. Support for linkage was sustained on chromosomes 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11, though at a more modest level. Family-based association analysis was consistent with the linkage results at all regions with linkage evidence, except 4q an 8q, but the results fell short of statistical significance. Three of the previously implicated regions-9q31, 10q21 and 10q24-showed substantial reduction in evidence of linkage. Our results strongly support 7q34 as a region harboring susceptibility locus for BP. Somewhat lesser, yet notable support was obtained for 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11. These regions could be considered prime candidates for future gene finding efforts.

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

Region	Statistical Values	Author Comments	Result Category
13q32	Association analysis: For marker D13S779, for BP2, allele 5, z-score = 2.3, FBAT P-value = 0.021458, perm P-value = 0.018622; linkage study: For marker D13S779, for BP2, ASP model, LOD = 0 in new pedigrees(N = 16); LOD = 2.09 in all pedigrees(N = 56); For marker D13S781, for BP2, ASP model, LOD = 0.13 in new pedigrees(N = 16); LOD = 2.69 in all pedigrees(N = 56)	Significant associations were found in BP2. Significant associations were found in BP2.	Positive
10q24	linkage study: for BP1, Dominant model, LOD = 0.11 in new pedigrees(N = 16); LOD = 0.98 in all pedigrees(N = 56)	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
10q21	linkage study: for BP2, Dominant model, LOD = 0 in new pedigrees(N = 16); LOD = 0.24 in all pedigrees(N = 56)	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
4q31	linkage study: for BP3, Dominant model, LOD = 0.25 in new pedigrees(N = 16); LOD = 1.94 in all pedigrees(N = 56)	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
2p13	Association analysis: For marker D2S337, for BP2, allele 7, z-score = 2.311, FBAT P-value = 0.02085, perm P-value = 0.021923; For marker D2S441, for BP2, allele 2, z-score = 2.508, FBAT P-value = 0.012143, perm P-value = 0.013457; For marker D2S2113, for BP2, allele 12, z-score = 2.325, FBAT P-value = 0.020064, perm P-value = 0.017097; linkage study: For marker D2S441, for BP2, Dominant model, LOD = 0.73 in new pedigrees(N = 16); LOD = 2.09 in all pedigrees(N = 56); For marker D2S1394, for BP2, ASP model, LOD = 1.78 in new pedigrees(N = 16); LOD = 2.77 in all pedigrees(N = 56)	Significant associations were found in BP2. Significant associations were found in BP2.	Positive
17q11	Association analysis: For marker D17S900, for BP1, allele 1, z-score = -2.077, FBAT P-value = 0.037806, perm P-value = 0.04025; For marker D17S921, for BP1, allele 7, z-score = 2.385, FBAT P-value = 0.017094, perm P-value = 0.018388; allele 3, z-score = -2.827, FBAT P-value = 0.004692, perm P-value = 0.004911;For marker D17S2196, for BP1, allele 5, z-score = 2.151, FBAT P-value = 0.031474, perm P-value = 0.031252; Global FBAT P-value = 0.021706, perm P-value = 0.031496; linkage study: For marker D17S921, for BP1, Dominant model, LOD = 1.22 in new pedigrees(N = 16); LOD = 0.85 in all pedigrees(N = 56); For marker D17S1303, for BP1, Dominant model, LOD = 0.83 in new pedigrees(N = 16); LOD = 2.07 in all pedigrees(N = 56)	Significant associations were found in BP1. Significant associations were found in BP1.	Positive
14q21	Association analysis: For marker D14S306, for BP2, allele 6, z-score = 2.05, FBAT P-value = 0.040409, perm P-value = 0.040958; For marker D14S1048, for BP2, allele 10, z-score = -2.044, FBAT P-value = 0.040951, perm P-value = 0.043478; allele 13, z-score = 2.646, FBAT P-value = 0.008151, perm P-value = 0.008258; For marker D14S1068, for BP2, allele 4, z-score = -2.553, FBAT P-value = 0.010674, perm P-value = 0.01256; allele 6, z-score = 2.077, FBAT P-value = 0.03782, perm P-value = 0.037744; allele 7, z-score = 2.443, FBAT P-value = 0.014556, perm P-value = 0.014445; Global FBAT P-value = 0.012825, perm P-value = 0.025058; linkage study: For marker D14S306, for BP2, ASP model, LOD = 0.65 in new pedigrees(N = 16); LOD = 1.9 in all pedigrees(N = 56)	Significant associations were found in BP2. Significant associations were found in BP2.	Positive
9q31	linkage study: for BP1, Dominant model, LOD = -0.02 in new pedigrees(N = 16); LOD = 0.42 in all pedigrees(N = 56)	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
8q13	linkage study: D8S2323, for BP2, Dominant model, LOD = 0 in new pedigrees(N = 16); LOD = 0.99 in all pedigrees(N = 56); D8S1136, for BP1, Dominant model, LOD = 1.89 in new pedigrees(N = 16); LOD = 1.62 in all pedigrees(N = 56)	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
7q34	For marker D7S1824: linkage study: for BP2, ASP model, LOD = 0.14 in new pedigrees(N = 16); LOD = 3.53 in all pedigrees(N = 56)	Significant linkage was found in this region for BPI. Significant linkage was found in this region for BPI.	Positive