Study Report

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Basic Info

Reference	Cichon, S.,2011 PMID: 21353194
Citation	Cichon, S., T. W. Muhleisen, et al. (2011). "Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder." Am J Hum Genet 88(3): 372-381.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	682 patients with BD and 1300 controls
SNP/Region/Marker Size	511,978 SNPs(499,494 autosomal and 12,484 X-chromosomal SNPs)
Predominant Ethnicity	Caucasian
Population	European

Detail Info

Sample Diagnosis	DSM
Sample Status	Subjects were recruited from consecutive admissions to psychiatric inpatient units at (1) The Central Institute of Mental Health, Mannheim (n=1081), (2) Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland (n=446), (3) Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania (n=237), (4) Civil Hospital Carlos Haya, Ma_laga, Spain (n=298), (5) Russian State Medical University, Moscow (n=329), and (6) Kosevo Hospital, Sarajevo, Bosnia and Herzegovina (n=125). All controls of replication I were also recruited by the abovementioned institutions. All GWAS controls were drawn from three populationbased epidemiological studies: (1) PopGen13 (n=490), (2) KORA14 (n=488), and (3) the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcification, and Lifestyle) (HNR,15 n=383).1.For GWAS:Germany I sample:German ancestry,682 BP patients,1300 controls,679 BPI patients2. For replication I:Germany II sample:German ancestry,361 BP patients,755 controls,138 BPI patients;Spain sample:Spanish ancestry,297 BP patients,391 controls,290 BPI patients;Russia sample:Russian ancestry,326 BP patients,329 controls,324 BPI patients;Romania sample:Romanian ancestry,227 BP patients,221 controls,227 BPI patients;Bosnia and Herzegovina/Serbia sample:Bosnian/Serbian ancestry,107 BP patients,113 controls,107 BPI patients3.For replication II:GAIN-EA/TGEN1 sample:European ancestry,2189 BP patients,1434 controls,2062 BPI patients;GermanyIII sample:German ancestry,497 BP patients,857 controls,376 BPI patients;France sample:French ancestry,471 BP patients,1758 controls,360 BPI patients;Iceland sample:Icelandic ancestry,422 BP patients,11487 controls,323 BPI patients;Australia sample:European ancestry,380 BP patients,1530 controls,291 BPI patients;Norway sample:Norwegian ancestry,203 BP patients,372 controls,128 BPI patients;Grand Total sample: 8441 BP patients,35362 controls,7222 BPI patients
Replication Size	Replication I:1729 patients with BD and 2313 controls;Replication II:6030 patients with BD and 31,749 controls
Technique	genotyping(HumanHap550v3 BeadArrays for GWAS;the iPLEX Gold assay for replication I)
Statistical Method	In the GWAS and replication I steps, analyses were computed with PLINK17 (version 1.05). Autosomal-wide analysis was performed via the TREND test with 1 degree of freedom (df). The X chromosome (females and males combined) was analyzed via the Wald test with 1 df. In replication I and the meta-analysis (GWAS and replication I), autosomal and X-chromosomal SNPs were investigated via the Cochran-Mantel-Haenszel (CMH) test.The CMH test was two-tailed for all analyses. To investigate the homogeneity of ORs for the replicated SNPs, we used the Breslow-Day test. In the replication II step, NCAN rs1064395 was investigated via logistic regression (assuming an additive effect), which was a two-tailed test. NCAN rs1064395 was also investigated with the use of a fixed-effects meta-analysis based on the weighted Z-score method,which was two-tailed for replication II samples (n=7) and for the combined analysis of all study samples (n=14).
Result Summary	In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 x 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 x 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 x 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

SNPs reported by this study for BD (count: 48)

SNP	Related Gene(s)	Risk Allele	Statistical Values	Author Comments	Result Category
rs16954276		T	For GWAS, P-value = 0.00000283, OR=0.58, for Replication I, P-value = 0.8144, OR=1.02, for combined sample(GWAS+Replication I), P-value = 0.0119, OR=0.86	Suggestive association was found. Suggestive association was found.	Trend
rs1725262	CAMTA1	C	For GWAS, P-value = 0.0000369, OR=1.35, for Replication I, P-value = 0.7453, OR=0.98, for combined sample(GWAS+Replication I), P-value = 0.0444, OR=1.09	No significant association was observed. No significant association was observed.	Negative
rs1317266		G	For GWAS, P-value = 0.0000548, OR=1.38, for Replication I, P-value = 0.9184, OR=1.01, for combined sample(GWAS+Replication I), P-value = 0.0175, OR=1.12	No significant association was observed. No significant association was observed.	Negative
rs1435442	STOX2	C	For GWAS, P-value = 0.0000059, OR=1.42, for Replication I, P-value = 0.7192, OR=1.02, for combined sample(GWAS+Replication I), P-value = 0.00511, OR=1.13	Suggestive association was found. Suggestive association was found.	Trend
rs1203860	RNF4	A	For GWAS, P-value = 0.0000308, OR=1.4, for Replication I, P-value = 0.1493, OR=0.92, for combined sample(GWAS+Replication I), P-value = 0.238, OR=1.05	No significant association was observed. No significant association was observed.	Negative
rs12123953	GIPC2	T	For GWAS, P-value = 0.0000638, OR=1.46, for Replication I, P-value = 0.5465, OR=0.96, for combined sample(GWAS+Replication I), P-value = 0.0866, OR=1.09	No significant association was observed. No significant association was observed.	Negative
rs11577112	IGSF21	G	For GWAS, P-value = 0.00000985, OR=1.5, for Replication I, P-value = 0.1138, OR=1.1, for combined sample(GWAS+Replication I), P-value = 0.000157, OR=1.21	Suggestive association was found. Suggestive association was found.	Trend
rs11764590	MAD1L1	T	For GWAS, P-value = 0.0000013, OR=1.47, for Replication I, P-value = 0.002, OR=1.18, for combined sample(GWAS+Replication I), P-value = 0.000000128, OR=1.26	Suggestive association was found. Suggestive association was found.	Trend
rs2774339	GNG4	T	For GWAS, P-value = 0.00000102, OR=0.71, for Replication I, P-value = 0.5772, OR=0.97, for combined sample(GWAS+Replication I), P-value = 0.00108, OR=0.88	Suggestive association was found. Suggestive association was found.	Trend
rs281413	ICAM3 RAVER1	A	For GWAS, P-value = 0.0000482, OR=0.72, for Replication I, P-value = 0.2806, OR=0.94, for combined sample(GWAS+Replication I), P-value = 0.00186, OR=0.87	No significant association was observed. No significant association was observed.	Negative
rs2398820	WNK2	G	For GWAS, P-value = 0.000017, OR=1.34, for Replication I, P-value = 0.9826, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0155, OR=1.1	No significant association was observed. No significant association was observed.	Negative
rs2654205		C	For GWAS, P-value = 0.0000666, OR=1.35, for Replication I, P-value = 0.1612, OR=1.08, for combined sample(GWAS+Replication I), P-value = 0.000625, OR=1.16	No significant association was observed. No significant association was observed.	Negative
rs1931364	WNK2	A	For GWAS, P-value = 0.000024, OR=1.45, for Replication I, P-value = 0.8423, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0249, OR=1.12	No significant association was observed. No significant association was observed.	Negative
rs2209263	TLE4	A	For GWAS, P-value = 0.0000344, OR=0.73, for Replication I, P-value = 0.0436, OR=0.9, for combined sample(GWAS+Replication I), P-value = 0.0000558, OR=0.84	No significant association was observed. No significant association was observed.	Negative
rs17530034		A	For GWAS, P-value = 0.00000675, OR=0.52, for Replication I, P-value = 0.3629, OR=1.09, for combined sample(GWAS+Replication I), P-value = 0.0689, OR=0.87	Suggestive association was found. Suggestive association was found.	Trend
rs1889339	WNK2	C	For GWAS, P-value = 0.0000076, OR=1.43, for Replication I, P-value = 0.966, OR=0.998, for combined sample(GWAS+Replication I), P-value = 0.02, OR=1.12	Suggestive association was found. Suggestive association was found.	Trend
rs11242396	KLHL3	G	For GWAS, P-value = 0.00000954, OR=1.38, for Replication I, P-value = 0.8961, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0164, OR=1.11	Suggestive association was found. Suggestive association was found.	Trend
rs1064395	NCAN HAPLN4	A	For GWAS, P-value = 0.00000342, OR=1.53, for Replication I, P-value = 0.000461, OR=1.23, for combined sample(GWAS+Replication I), P-value = 0.0000000302, OR=1.31	Suggestive association was found. Suggestive association was found.	Trend
rs10500683		C	For GWAS, P-value = 0.0000375, OR=0.76, for Replication I, P-value = 0.5162, OR=0.97, for combined sample(GWAS+Replication I), P-value = 0.00419, OR=0.9	No significant association was observed. No significant association was observed.	Negative
rs10426528	LYPD5	T	For GWAS, P-value = 0.0000669, OR=1.31, for Replication I, P-value = 0.8296, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0358, OR=1.08	No significant association was observed. No significant association was observed.	Negative
rs10278591	MAD1L1	T	For GWAS, P-value = 0.00000605, OR=1.43, for Replication I, P-value = 0.0348, OR=1.12, for combined sample(GWAS+Replication I), P-value = 0.0000181, OR=1.21	Suggestive association was found. Suggestive association was found.	Trend
rs10231989	CCDC132	C	For GWAS, P-value = 0.0000278, OR=1.33, for Replication I, P-value = 0.7172, OR=0.98, for combined sample(GWAS+Replication I), P-value = 0.039, OR=1.08	No significant association was observed. No significant association was observed.	Negative
rs779279	FGF12	A	For GWAS, P-value = 0.0000425, OR=0.76, for Replication I, P-value = 0.0402, OR=0.91, for combined sample(GWAS+Replication I), P-value = 0.0000639, OR=0.86	No significant association was observed. No significant association was observed.	Negative
rs843319	MBOAT1	G	For GWAS, P-value = 0.0000445, OR=1.35, for Replication I, P-value = 0.3004, OR=0.95, for combined sample(GWAS+Replication I), P-value = 0.166, OR=1.06	No significant association was observed. No significant association was observed.	Negative
rs930906		A	For GWAS, P-value = 0.000126, OR=2.7, for Replication I, P-value = 0.1596, OR=1.23, for combined sample(GWAS+Replication I), P-value = 0.00228, OR=1.47	No significant association was observed. No significant association was observed.	Negative
rs9322993	GEMIN2	T	For GWAS, P-value = 0.0000756, OR=1.75, for Replication I, P-value = 0.0382, OR=1.23, for combined sample(GWAS+Replication I), P-value = 0.0000754, OR=1.37	No significant association was observed. No significant association was observed.	Negative
rs705648	PECR	C	For GWAS, P-value = 0.0000676, OR=1.35, for Replication I, P-value = 0.0277, OR=0.9, for combined sample(GWAS+Replication I), P-value = 0.732, OR=1.01	No significant association was observed. No significant association was observed.	Negative
rs7229918		G	For GWAS, P-value = 0.0000508, OR=1.35, for Replication I, P-value = 0.8914, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0298, OR=1.1	No significant association was observed. No significant association was observed.	Negative
rs7268	HBEGF	T	For GWAS, P-value = 0.0000704, OR=1.3, for Replication I, P-value = 0.597, OR=0.98, for combined sample(GWAS+Replication I), P-value = 0.0721, OR=1.07	No significant association was observed. No significant association was observed.	Negative
rs7297212	NTF3	A	For GWAS, P-value = 0.000024, OR=1.56, for Replication I, P-value = 0.3676, OR=1.07, for combined sample(GWAS+Replication I), P-value = 0.00223, OR=1.19	No significant association was observed. No significant association was observed.	Negative
rs985409	LHFPL3	G	For GWAS, P-value = 0.0000652, OR=1.31, for Replication I, P-value = 0.0206, OR=1.11, for combined sample(GWAS+Replication I), P-value = 0.0000389, OR=1.17	No significant association was observed. No significant association was observed.	Negative
rs9944047		C	For GWAS, P-value = 0.0000633, OR=0.76, for Replication I, P-value = 0.744, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0121, OR=0.91	No significant association was observed. No significant association was observed.	Negative
rs4849303	ACOXL RPL5P9	T	For GWAS, P-value = 0.0000563, OR=0.76, for Replication I, P-value = 0.2354, OR=1.06, for combined sample(GWAS+Replication I), P-value = 0.2, OR=0.95	No significant association was observed. No significant association was observed.	Negative
rs4844367		A	For GWAS, P-value = 0.000189, OR=0.75, for Replication I, P-value = 0.1454, OR=0.93, for combined sample(GWAS+Replication I), P-value = 0.00111, OR=0.87	No significant association was observed. No significant association was observed.	Negative
rs508208	GNG4	G	For GWAS, P-value = 0.00000735, OR=0.73, for Replication I, P-value = 0.3894, OR=0.96, for combined sample(GWAS+Replication I), P-value = 0.000939, OR=0.88	Suggestive association was found. Suggestive association was found.	Trend
rs502224	MACROD1	T	For GWAS, P-value = 0.000031, OR=1.43, for Replication I, P-value = 0.7962, OR=1.02, for combined sample(GWAS+Replication I), P-value = 0.00915, OR=1.14	No significant association was observed. No significant association was observed.	Negative
rs422159	TRPV3	A	For GWAS, P-value = 0.0000376, OR=1.33, for Replication I, P-value = 0.056, OR=1.09, for combined sample(GWAS+Replication I), P-value = 0.0000892, OR=1.16	No significant association was observed. No significant association was observed.	Negative
rs3996329	MAD1L1	T	For GWAS, P-value = 0.0000132, OR=1.45, for Replication I, P-value = 0.1124, OR=1.09, for combined sample(GWAS+Replication I), P-value = 0.000172, OR=1.19	No significant association was observed. No significant association was observed.	Negative
rs4743473	PPP3R2 GRIN3A	A	For GWAS, P-value = 0.0000237, OR=1.32, for Replication I, P-value = 0.5348, OR=1.03, for combined sample(GWAS+Replication I), P-value = 0.00393, OR=1.12	No significant association was observed. No significant association was observed.	Negative
rs4461243		A	For GWAS, P-value = 0.0000662, OR=1.31, for Replication I, P-value = 0.7949, OR=0.99, for combined sample(GWAS+Replication I), P-value = 0.0451, OR=1.08	No significant association was observed. No significant association was observed.	Negative
rs6821225		C	For GWAS, P-value = 0.0000407, OR=1.31, for Replication I, P-value = 0.275, OR=1.05, for combined sample(GWAS+Replication I), P-value = 0.00171, OR=1.13	No significant association was observed. No significant association was observed.	Negative
rs6767011	STAC	A	For GWAS, P-value = 0.0000142, OR=1.54, for Replication I, P-value = 0.2001, OR=0.91, for combined sample(GWAS+Replication I), P-value = 0.185, OR=1.08	No significant association was observed. No significant association was observed.	Negative
rs7023951	ZNF618	T	For GWAS, P-value = 0.0000386, OR=1.37, for Replication I, P-value = 0.4202, OR=1.05, for combined sample(GWAS+Replication I), P-value = 0.00266, OR=1.14	No significant association was observed. No significant association was observed.	Negative
rs6943047		T	For GWAS, P-value = 0.0000114, OR=1.5, for Replication I, P-value = 1, OR=1, for combined sample(GWAS+Replication I), P-value = 0.0128, OR=1.14	No significant association was observed. No significant association was observed.	Negative
rs6506625		A	For GWAS, P-value = 0.000044, OR=0.75, for Replication I, P-value = 0.524, OR=0.97, for combined sample(GWAS+Replication I), P-value = 0.00494, OR=0.9	No significant association was observed. No significant association was observed.	Negative
rs6488297		A	For GWAS, P-value = 0.00000371, OR=1.51, for Replication I, P-value = 0.2994, OR=1.07, for combined sample(GWAS+Replication I), P-value = 0.000552, OR=1.19	Suggestive association was found. Suggestive association was found.	Trend
rs6715508	PARD3B	T	For GWAS, P-value = 0.00000937, OR=1.45, for Replication I, P-value = 0.5774, OR=0.97, for combined sample(GWAS+Replication I), P-value = 0.0422, OR=1.1	Suggestive association was found. Suggestive association was found.	Trend
rs6547829	BRE	T	For GWAS, P-value = 0.0000721, OR=1.59, for Replication I, P-value = 0.0134, OR=1.22, for combined sample(GWAS+Replication I), P-value = 0.000025, OR=1.32	No significant association was observed. No significant association was observed.	Negative

Genes reported by this study for BD (count: 7)

Gene	Statistical Values/Author Comments	Result Category
TLE4	No positive signal in this gene was observed for BD. No positive signal in this gene was observed for BD.	Negative
MAD1L1	In summary, the present study has identified a potential BD susceptibility factor, MAD1L1. In summary, the present study has identified a potential BD susceptibility factor, MAD1L1.	Trend
FGF12	No positive signal in this gene was observed for BD. No positive signal in this gene was observed for BD.	Negative
NCAN	In summary, the present study has identified a susceptibility factor , NCAN for BD. In summary, the present study has identified a susceptibility factor , NCAN for BD.	Positive
GEMIN2	No positive signal in this gene was observed for BD. No positive signal in this gene was observed for BD.	Negative
LHFPL3	No positive signal in this gene was observed for BD. No positive signal in this gene was observed for BD.	Negative
BRE	No positive signal in this gene was observed for BD. No positive signal in this gene was observed for BD.	Negative