Study Report

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Basic Info

Reference	Jamain, S., 2014 PMID: 25111785
Citation	Jamain, S., et al. (2014). "Common and rare variant analysis in early-onset bipolar disorder vulnerability." PLoS One 9(8): e104326.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	GWAS: 211 patients of French and 1719 controls
SNP/Region/Marker Size	3.9 million SNPs
Predominant Ethnicity	Caucasian
Population	French, German

Detail Info

Sample Diagnosis	DMS-IV
Sample Status	French sample: Two hundred and twenty patients of French descent with at least three grandparents from mainland France were collected through a French national network for mental health (Fondation FondaMental) in three university-affiliated psychiatry departments (Paris-CreÂ´teil, Bordeaux and Nancy) as previously described. All patients met DSM-IV criteria for BD type I (N=172), type II (N=46) or BD not otherwise specified (N=2) before the age of 22. German sample: One hundred and sixty-seven German patients were recruited from consecutive admissions to the psychiatric inpatient units of the Central Institute of Mental Health in Mannheim and the Department of Psychiatry and Psychotherapy of the University of Bonn (BOMA bipolar study). These patients received a lifetime diagnosis of BD type I based on DSM-IV criteria and had an age at onset lower than 22.
Replication Size	Replication in a German sample: 159 patients and 998 controls. Additional replication studies in two datasets: the WTCCC (764 patients and 2938 controls) and the GAIN-TGen cohorts (1524 patients and 1436 controls)
Technique	French and German cases were genotyped at the CNG, using HumanHap550 or Human 610-Quad BeadArrays and the Infinium II assay (Illumina, San Diego, CA, USA). Control samples were genotyped on HumanHap300 (N=2503) or on HumanHap550 BeadArrays (N=380).
Statistical Method	Basic case/control association analyses were performed using the PLINK software v1.07. A haplotype analysis was performed on the two most associated regions using sliding windows of two to five SNPs shifting by one SNP at a time. We tested for case/control haplotype-based association using a chi-square test with one degree of freedom. Only window with best P-values are reported for each region. Imputation data were based on the 3967651 SNPs genotyped in 90 subjects of the CEU population of the HapMap project. Imputation was performed using PLINK and consisted in estimating the allele frequencies of an ungenotyped SNP based on its surrounding haplotypic background. Copy number variations were detected by fluorescence level comparison through the chromosome, using the SnipPeep software (R. Toro, Pasteur Institute, France). The deletion in PLCXD3 was confirmed by quantitative PCR analysis using one internal and two external couples of primers and Mesa Green qPCR master mix plus (Eurogentec, Liege, Belgium).
Result Summary	Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway ( PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC and the GAIN-TGen cohorts and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability.

SNPs reported by this study for BD (count: 38)

SNP	Related Gene(s)	Risk Allele	Statistical Values	Author Comments	Result Category
rs2565666	PLEKHA5 AEBP2		Replication studies on the WTCCC and the GAIN-Tgen cohorts: P-value=0.03, OR=1.22	This SNP also showed a nominal P-value. This SNP also showed a nominal P-value.	Positive
rs625487	PLCXD3 OXCT1		Replication studies on the WTCCC and the GAIN-Tgen cohorts: P-value=0.02, OR=1.15	Two SNPs on chromosome 5p13 in lower linkage disequilibrium ...... Two SNPs on chromosome 5p13 in lower linkage disequilibrium (r²=0.65) with rs822135 showed a nominal P-value. More...	Positive
rs633407	PLCXD3 OXCT1		Replication studies on the WTCCC and the GAIN-Tgen cohorts: P-value=0.02, OR=1.15	Two SNPs on chromosome 5p13 in lower linkage disequilibrium ...... Two SNPs on chromosome 5p13 in lower linkage disequilibrium (r²=0.65) with rs822135 showed a nominal P-value. More...	Positive
rs2970836	PLEKHA5		German sample: P-value=5.3E-06, OR=1.76	The most associated SNP in the German sample was located on ...... The most associated SNP in the German sample was located on chromosome 12 upstream to the PLEKHA5 gene. More...	Trend
rs10743315	PLEKHA5		Imputation: P-value=2.1E-07, OR=1.61	After imputation, we observed an increased signal for chromo...... After imputation, we observed an increased signal for chromosome 12 with the lowest estimated P-value for rs10743315 located in PLEKHA5. More...	Trend
rs12645446		C	French population: P-value=4.1E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs823692	RIOK1 DSP	C	French population: P-value=4.5E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs2829644	CD365222	A	French population: P-value=2.34E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs1393941	CERS3	C	French population: P-value=2.5E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs4716990		G	French sample:Â P-value=6.12E-04,Â OR=1.45;Â German sample:Â P-value=1.99E-02,Â OR=1.34;Â Meta-analysis:Â P-value_meta=4.04E-05,Â OR_meta=1.4	The strongest association observed in the mega-analysis for ...... The strongest association observed in the mega-analysis for SNPs tested in at least three of the four populations was observed on chromosome 7q36.3 in a gene desert. More...	Trend
rs12505439	LINC00499	A	French sample:Â P-value=9.91E-03,Â OR=1.32;Â German sample:Â P-value=1.05E-03,Â OR=1.5;Â Meta-analysis:Â P-value_meta=4.48E-05,Â OR_meta=1.4	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs3739657	FRMD3	C	French sample:Â P-value=2.21E-03,Â OR=0.71;Â German sample:Â P-value=6.87E-03,Â OR=0.7;Â Meta-analysis:Â P-value_meta=4.74E-05,Â OR_meta=0.71	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs10096683	SGCZ	G	French population: P-value=4.11E-06, OR=2.26	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs12031354	C1orf110 RGS4	G	French population: P-value=4.6E-06	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs763532	NWD2	T	French population: P-value=8.55E-06	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs1108610	LINC01141	G	French population: P-value=9.99E-06	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs1504772	CSMD1	A	French population: P-value=1.78E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs5930575	HS6ST2	A	French population: P-value=1.83E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs6028791	LINC01370 BQ574468	C	French population: P-value=1.94E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs2829656	CD365222	T	French population: P-value=1.94E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs8019549	MIPOL1	A	French population: P-value=1.95E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs34116	RASGRF2	T	French population: P-value=2.02E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs291504	AW295978 BU188154	G	French population: P-value=2.11E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs10135285	MIPOL1	G	French population: P-value=2.13E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs1250062	LINC00607	T	French population: P-value=2.14E-05	17 SNPs showed a nominal P<5E-05, suggesting these loci may ...... 17 SNPs showed a nominal P<5E-05, suggesting these loci may be associated with vulnerability to early-onset forms of BD. More...	Trend
rs2961365	AEBP2 PLEKHA5	T	French sample:Â P-value=1.88E-04,Â OR=1.58;Â German sample:Â P-value=2.12E-03,Â OR=1.56;Â Meta-analysis:Â P-value_meta=1.58E-06,Â OR_meta=1.57	The largest difference in allele frequencies between cases a...... The largest difference in allele frequencies between cases and controls was observed for chromosome 12 (rs2961365) with no evidence of heterogeneity between the two cohorts. More...	Trend
rs10512793	OXCT1	C	French sample:Â P-value=1.24E-03,Â OR=1.54;Â German sample:Â P-value=4.64E-04,Â OR=1.72;Â Meta-analysis:Â P-value_meta=2.68E-06,Â OR_meta=1.61	The second strongest association with no heterogeneity was o...... The second strongest association with no heterogeneity was observed for chromosome 5p13. More...	Trend
rs3752823	PLEKHA5 AEBP2	A	French sample:Â P-value=2.03E-03,Â OR=1.58;Â German sample:Â P-value=1.70E-04,Â OR=1.89;Â Meta-analysis:Â P-value_meta=2.09E-06,Â OR_meta=1.71	This SNP showed a difference in allele frequencies at P<5E-0...... This SNP showed a difference in allele frequencies at P<5E-05. More...	Trend
rs7305762	AEBP2 PLEKHA5	G	French sample:Â P-value=2.46E-04,Â OR=1.57;Â German sample:Â P-value=3.53E-03,Â OR=1.53;Â Meta-analysis:Â P-value_meta=3.26E-06,Â OR_meta=1.55	This SNP showed a difference in allele frequencies at P<5E-0...... This SNP showed a difference in allele frequencies at P<5E-05. More...	Trend
rs2900433	AEBP2 PLEKHA5	T	French sample:Â P-value=4.13E-04,Â OR=1.55;Â German sample:Â P-value=2.01E-03,Â OR=1.57;Â Meta-analysis:Â P-value_meta=3.13E-06,Â OR_meta=1.56	This SNP showed a difference in allele frequencies at P<5E-0...... This SNP showed a difference in allele frequencies at P<5E-05. More...	Trend
rs952076	GPM6B	T	French sample:Â P-value=2.61E-03,Â OR=0.65;Â German sample:Â P-value=5.94E-04,Â OR=0.56;Â Meta-analysis:Â P-value_meta=7.48E-06,Â OR_meta=0.61	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs12500759	SORCS2	T	French sample:Â P-value=7.54E-04,Â OR=0.66;Â German sample:Â P-value=2.76E-03,Â OR=0.66;Â Meta-analysis:Â P-value_meta=7.40E-06,Â OR_meta=0.66	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs4764470	PLEKHA5 AEBP2	A	French sample:Â P-value=2.55E-04,Â OR=1.53;Â German sample:Â P-value=1.84E-02,Â OR=1.39;Â Meta-analysis:Â P-value_meta=1.73E-05,Â OR_meta=1.47	This SNP showed a difference in allele frequencies at P<5E-0...... This SNP showed a difference in allele frequencies at P<5E-05. More...	Trend
rs822135	OXCT1	A	French sample:Â P-value=8.12E-04,Â OR=0.68;Â German sample:Â P-value=5.54E-03,Â OR=0.69;Â Meta-analysis:Â P-value_meta=1.50E-05,Â OR_meta=0.68	This SNP showed a difference in allele frequencies at P<5E-0...... This SNP showed a difference in allele frequencies at P<5E-05. More...	Trend
rs7185187	VAC14	T	French sample:Â P-value=5.99E-04,Â OR=1.8;Â German sample:Â P-value=9.63E-03,Â OR=1.65;Â Meta-analysis:Â P-value_meta=2.24E-05,Â OR_meta=1.73	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs7608161	YWHAQ	G	French sample:Â P-value=2.90E-03,Â OR=1.38;Â German sample:Â P-value=1.68E-03,Â OR=1.5;Â Meta-analysis:Â P-value_meta=1.82E-05,Â OR_meta=1.43	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs13091545	DNAH1	G	French sample:Â P-value=1.73E-04,Â OR=1.57;Â German sample:Â P-value=4.64E-02,Â OR=1.35;Â Meta-analysis:Â P-value_meta=3.24E-05,Â OR_meta=1.48	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend
rs6857347	LINC00499	G	French sample:Â P-value=6.80E-03,Â OR=0.75;Â German sample:Â P-value=7.62E-04,Â OR=0.66;Â Meta-analysis:Â P-value_meta=2.40E-05,Â OR_meta=0.71	It showed little evidence for association with BD. It showed little evidence for association with BD.	Trend

Haplotypes reported by this study for BD (count: 1)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs624097 - rs316762 - rs10512793		OXCT1 PLCXD3	P_meta=2.6E-07	A more significant difference between patients and controls ...... A more significant difference between patients and controls was observed on chromosome 5p13 for the combination of rs624097-rs316762-rs10512793, for which an overall P_meta=2.6E-07 was observed. More...	Trend

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

Gene	Statistical Values/Author Comments	Result Category
DSP	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
HS6ST2	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
NWD2	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
CERS3	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
BU188154	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
C1orf110	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
CD365222	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
CSMD1	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
SGCZ	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
PLEKHA5	Significant association of SNP in this gene with BD was observed. Significant association of SNP in this gene with BD was observed.	Positive
AEBP2	Significant association of SNP in this gene with BD was observed. Significant association of SNP in this gene with BD was observed.	Positive
OXCT1	Significant association of SNP in this gene with BD was observed. Significant association of SNP in this gene with BD was observed.	Positive
MIPOL1	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
RASGRF2	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
RGS4	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
RIOK1	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
PLCXD3	Significant association of SNP in this gene with BD was observed. Significant association of SNP in this gene with BD was observed.	Positive
LINC01141	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
AW295978	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
BQ574468	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
LINC01370	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend
LINC00607	It showed nominal evidence for association with BD. It showed nominal evidence for association with BD.	Trend