Study Report

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Basic Info

Reference	Cassidy, F.,2007 PMID: 17455214
Citation	Cassidy, F., C. Zhao, et al. (2007). "Genome-wide scan of bipolar disorder and investigation of population stratification effects on linkage: support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13." Am J Med Genet B Neuropsychiatr Genet 144B(6): 791-801.
Disease Type	Bipolar Disorder
Study Design	pedigree
Study Type	Genome-wide linkage study
Sample Size	60 independent broadly defined ASPs (32 narrow) and a maximum of 98 broadly defined sib pairs (all possible, 38 narrow).
SNP/Region/Marker Size	401 microsatellite markers for whole genome wide
Predominant Ethnicity	Caucasian
Population	Irish

Detail Info

Sample Diagnosis	DSM
Sample Status	Sixty ASP families, all of Irish origin, were recruited by a single research group at St. Patrick's Hospital, Dublin, Ireland. All participants were interviewed by a trained psychiatric research nurse using the Schedule for Affective Disorders and Schizophrenia (Lifetime version; SADS-LB) [Endicott and Spitzer, 1978] and were diagnosed according to DSM-IV criteria [Association 1994]. Sib pairs were ascertained by a bipolar type I (BPI) proband and a sibling with an affection status of BPI, bipolar type II (BPII), recurrent major depression (RUP) or schizoaffective disorder (SA).
Technique	genotyping
Statistical Method	As BPD is a complex disorder, linkage analysis was performed using a non-parametric analysis which examines the number of alleles identical by descent (IBD) between sib pairs in a pedigree and does not require specification of an inheritance model.
Result Summary	Our most significant result was at 14q24 which yielded a non-parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P-value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22-24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE-Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.

Regions reported by this study for BD (count: 22)

Region	Statistical Values	Author Comments	Result Category
1q42	Pairwise Linkage Analysis: narrow model, NPL = 1.4675, P-value = 0.072526	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
1p21	Multipoint Linkage Analysis: Broad model, NPL = 1.39172, P-value = 0.08084	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
21q21	Pairwise Linkage Analysis: narrow model, NPL = 1.95952, P-value = 0.026101; Multipoint Linkage Analysis: narrow model, NPL = 1.90954, P-value = 0.029272; Pairwise Linkage Analysis: Broad model, NPL = 1.37995, P-value = 0.084357; Structure-Guided Linkage Analysis: Broad model: NPL = 1.63, P-value = 0.05 for all families.; NPL = 1.12, P-value = 0.13 for families.; Narrow model: NPL = 1.99, P-value = 0.024 for all families.; NPL = 1.47, P_value = 0.072 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
20p12	Pairwise Linkage Analysis: narrow model, NPL = 2.11314, P-value = 0.016765; Structure-Guided Linkage Analysis: Broad model: NPL = 0.6, P-value = 0.27 for all families.; NPL = 0.65, P-value = 0.25 for families.; Narrow model: NPL = 2.14, P-value = 0.016 for all families.; NPL = 2.11, P_value = 0.016 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
15q12	Multipoint Linkage Analysis: Broad model, NPL = 1.489, P-value = 0.068888	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
14q24	Multipoint Linkage Analysis: For marker GATA169E06ZP, Broad model, NPL = 2.24775, P-value = 0.012692; For marker D14S588, narrow model, NPL = 3.27677, P-value = 0.000598	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
17p11	Multipoint Linkage Analysis: narrow model, NPL = 1.5782, P-value = 0.058613	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
16p13	Multipoint Linkage Analysis: narrow model, NPL = 1.99199, P-value = 0.024227; Pairwise Linkage Analysis: Broad model, NPL = 1.49168, P-value = 0.068545; narrow model, NPL = 2.23042, P-value = 0.013655; Structure-Guided Linkage Analysis: Broad model: NPL = 1.77, P-value = 0.04 for all families.; NPL = 1.77, P-value = 0.039 for families.; Narrow model: NPL = 2.23, P-value = 0.014 for all families.; NPL = 2.75, P_value = 0.003 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
12q24	Multipoint Linkage Analysis: For marker D12S2082, Broad model, NPL = 1.78615, P-value = 0.037651; Pairwise Linkage Analysis: Broad model, NPL = 1.49254, P-value = 0.068397; For marker D12S2078, narrow model, NPL = 2.20186, P-value = 0.014663	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
14q23	Pairwise Linkage Analysis: narrow model, NPL = 1.85278, P-value = 0.03315	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
13q32	Multipoint Linkage Analysis: Broad model, NPL = 1.75457, P-value = 0.039028; Pairwise Linkage Analysis: Broad model, NPL = 2.15582, P-value = 0.015295; Structure-Guided Linkage Analysis: Broad model: NPL = 2.25, P-value = 0.012 for all families.; NPL = 1.65, P-value = 0.049 for families.; Narrow model: NPL = 0.89, P-value = 0.19 for all families.; NPL = 0.69, P_value = 0.25 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
8q13	Multipoint Linkage Analysis: narrow model, NPL = 1.74459, P-value = 0.041765	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
9p21	Multipoint Linkage Analysis: Broad model, NPL = 2.41114, P-value = 0.008263; Structure-Guided Linkage Analysis: Broad model: NPL = 1.64, P-value = 0.051 for all families.; NPL = 2.35, P-value = 0.01 for families.; Narrow model: NPL = 0.69, P-value = 0.24 for all families.; NPL = 1.33, P_value = 0.09 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
9q21	Pairwise Linkage Analysis: Broad model, NPL = 2.17142, P-value = 0.015383; narrow model, NPL = 1.62595, P-value = 0.053312; Structure-Guided Linkage Analysis: Broad model: NPL = 2.16, P-value = 0.016 for all families.; NPL = 1.68, P-value = 0.045 for families.; Narrow model: NPL = 1.62, P-value = 0.054 for all families.; NPL = 1.8, P_value = 0.037 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
6p22	Multipoint Linkage Analysis: Broad model, NPL = 1.88278, P-value = 0.030438	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
6p23	Multipoint Linkage Analysis: narrow model, NPL = 2.10507, P-value = 0.018547; Pairwise Linkage Analysis: Broad model, NPL = 1.57752, P-value = 0.057993; narrow model, NPL = 1.90567, P-value = 0.029474	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
6p24	Structure-Guided Linkage Analysis: Broad model: NPL = 1.6, P-value = 0.06 for all families.; NPL = 1.51, P-value = 0.07 for families.; Narrow model: NPL = 1.92, P-value = 0.029 for all families.; NPL = 2.12, P_value = 0.018 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
7q36	Multipoint Linkage Analysis: Broad model, NPL = 2.07477, P-value = 0.018683; narrow model, NPL = 2.11033, P-value = 0.018353; Pairwise Linkage Analysis: Broad model, NPL = 1.79413, P-value = 0.035802; narrow model, NPL = 1.91464, P-value = 0.028855; Structure-Guided Linkage Analysis: Broad model: NPL = 1.83, P-value = 0.034 for all families.; NPL = 1.8, P-value = 0.036 for families.; Narrow model: NPL = 1.93, P-value = 0.028 for all families.; NPL = 1.89, P_value = 0.03 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
2p25	Multipoint Linkage Analysis: Broad model, NPL = 1.30302, P-value = 0.096817; Structure-Guided Linkage Analysis: Broad model: NPL = 1.56, P-value = 0.06 for all families.; NPL = 2.35, P-value = 0.01 for families.; Narrow model: NPL = 0.31, P-value = 0.37 for all families.; NPL = 0.53, P_value = 0.29 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
2q11	Multipoint Linkage Analysis: narrow model, NPL = 2.06958, P-value = 0.02023Pairwise Linkage Analysis: narrow model, NPL = 1.5164, P-value = 0.065958	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend
2q24	Pairwise Linkage Analysis: Broad model, NPL = 1.66419, P-value = 0.048689	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
4q21	Multipoint Linkage Analysis: For marker D4S3243, Broad model, NPL = 2.23315, P-value = 0.013191; narrow model, NPL = 1.54987, P-value = 0.062008; Structure-Guided Linkage Analysis: For marker D4S2361, Broad model: NPL = 1.02, P-value = 0.154 for all families.; NPL = 1.99, P-value = 0.024 for families.; Narrow model: NPL = 0.83, P-value = 0.2 for all families.; NPL = 0.79, P_value = 0.21 for 60% homogeneous families.	There is a trend for Significant linkage. There is a trend for Significant linkage.	Trend