Study Report

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Basic Info

Reference	Baum, A. E., 2008 (a) PMID: 17486107
Citation	Baum, A. E., N. Akula, et al. (2008). "A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder." Mol Psychiatry 13(2): 197-207.
Disease Type	Bipolar I Disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	461 BD and 563 controls
SNP/Region/Marker Size	555,235 SNPs
Predominant Ethnicity	Caucasian
Population	NIMH collection and German
Gender	Test sample comprised 461 bipolar I patients (64 female) and 563 controls (44 female). The replication ('German') sample consisted of 772 bipolar I patients (53 female) and 876 control individuals (47 female).

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Our test sample ('NIMH') consisted of 461 unrelated bipolar I probands selected from families with at least one affected sibling pair. The replication ('German') sample consisted of 772 bipolar I patients recruited from consecutive hospital. All patients had a DSM-IV diagnosis of bipolar I disorder necessitating inpatient treatment. Over 96% reported that their parents and all four grandparents were born in Germany.
Replication Size	The replication ('German') sample consisted of 772 bipolar I patients and 876 control individuals.
Technique	Pooled DNA was concentrated using Micron YM-100 Filter columns before genotyping.
Statistical Method	We calculated normalized allele frequencies from raw intensity data and averaged data across replicate pools to obtain a relative allele frequency (RAF) estimate for each SNP in each pool. SNP-pool combinations with a variance between replicate pools of > 2% were excluded. We tested (t-test) the null hypothesis that the transformed RAF for cases was equal to the transformed RAF for the controls. In order to minimize false positives due to multiple testing, we employed a replication design.
Result Summary	A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P= 1.5E-08, experiment-wide P < 0.01, OR= 1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway.

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

SNP	Related Gene(s)	Risk Allele	Statistical Values	Author Comments	Result Category
rs13414801	BRE	C	P-value = 0.001 when genotyped individually in the test sample (NIMH); P-value = 0.913 when individually genotyped in the Replication sample (German); P-value = 0.056 in the combined dataset. OR (95% CI)=NS		Negative
rs13218303	GRM1	G	P-value = 0.082 when genotyped individually in the test sample (NIMH)		Negative
rs12608087	LAMA3	C	P-value = 0.011 when genotyped individually in the test sample (NIMH); P-value = 0.439 when individually genotyped in the Replication sample (German); P-value = 0.03 in the combined dataset. OR (95% CI)=1.25 (1.02-1.52)		Negative
rs12410676	VAV3	G	P-value = 0.061 when genotyped individually in the test sample (NIMH); P-value = 0.024 when individually genotyped in the Replication sample (German); P-value = 0.004 in the combined dataset. OR (95% CI)=1.28 (1.09-1.51)		Negative
rs1818290	RBFOX1	G	P-value = 0.657 when genotyped individually in the test sample (NIMH)		Negative
rs17477151	LRRC4C	G	P-value = 0.027 when genotyped individually in the test sample (NIMH); P-value = 0.285 when individually genotyped in the Replication sample (German); P-value = 0.03 in the combined dataset. OR (95% CI)=1.26 (1.03-1.55)		Negative
rs17350383	HDAC9	T	P-value = 0.218 when genotyped individually in the test sample (NIMH)		Negative
rs17125698	FOXN3	C	P-value = 0.028 when genotyped individually in the test sample (NIMH); P-value = 0.049 when individually genotyped in the Replication sample (German); P-value = 0.003 in the combined dataset. OR (95% CI)=1.26 (1.08-1.47)		Negative
rs10500336	RBFOX1	G	P-value = 0.018 when genotyped individually in the test sample (NIMH); P-value = 0.38 when individually genotyped in the Replication sample (German); P-value = 0.022 in the combined dataset. OR (95% CI)=1.20 (1.02-1.41)		Negative
rs1012053	DGKH	A	P-value = 0.0002 when genotyped individually in the test sample (NIMH); P-value = 1.5E-05 when individually genotyped in the Replication sample (German); P-value = 1.5E-08 in the combined dataset. OR (95% CI)=1.59 (1.35-1.87)	significant at the P < 0.05 level in both samples. This SNP ...... significant at the P < 0.05 level in both samples. This SNP is significant at the experiment-wide P < 0.01 after Bonferroni correction of the combined results for the total number of SNPs studied. More...	Positive
rs1170191	DGKH	C	P-value = 0.003 when genotyped individually in the test sample (NIMH); P-value = 0.0003 when individually genotyped in the Replication sample (German); P-value = 3.7E-08 in the combined dataset. OR (95% CI)=1.42 (1.23-1.65)	significant at the P < 0.05 level in both samples. significant at the P < 0.05 level in both samples.	Positive
rs1131171	NCL SNORD82	G	P-value = 0.048 when genotyped individually in the test sample (NIMH); P-value = 0.104 when individually genotyped in the Replication sample (German); P-value = 0.013 in the combined dataset. OR (95% CI)=1.20 (1.04-1.38)		Negative
rs11021955	GALNT18	C	P-value = 0.003 when genotyped individually in the test sample (NIMH); P-value = 0.059 when individually genotyped in the Replication sample (German); P-value = 0.001 in the combined dataset. OR (95% CI)=1.33 (1.12-1.56)		Negative
rs10937823	SORCS2	C	P-value = 0.001 when genotyped individually in the test sample (NIMH); P-value = 0.004 when individually genotyped in the Replication sample (German); P-value = 0.000014 in the combined dataset. OR (95% CI)=1.67 (1.32-2.13)	significant at the P < 0.05 level in both samples. significant at the P < 0.05 level in both samples.	Trend
rs437179	NELFE SKIV2L	G	P-value = 0.018 when genotyped individually in the test sample (NIMH); P-value = 0.053 when individually genotyped in the Replication sample (German); P-value = 0.003 in the combined dataset. OR (95% CI)=1.21 (1.07-1.36)		Negative
rs4398100	PLCG2	C	P-value = 0.069 when genotyped individually in the test sample (NIMH); P-value = 0.106 when individually genotyped in the Replication sample (German); P-value = 0.014 in the combined dataset. OR (95% CI)=1.20 (1.04-1.39)		Negative
rs4411993	SORCS2 MIR4274	C	P-value = 0.003 when genotyped individually in the test sample (NIMH); P-value = 0.03 when individually genotyped in the Replication sample (German); P-value = 0.0005 in the combined dataset. OR (95% CI)=1.35 (1.14-1.61)	significant at the P < 0.05 level in both samples. significant at the P < 0.05 level in both samples.	Negative
rs4813030	PSMF1	C	P-value = 0.004 when genotyped individually in the test sample (NIMH); P-value = 0.545 when individually genotyped in the Replication sample (German); P-value = 0.023 in the combined dataset. OR (95% CI)=1.18 (1.03-1.35)		Negative
rs6501822	LLGL2	G	P-value = 0.0192 when genotyped individually in the test sample (NIMH)		Negative
rs7204975	RBFOX1 RNU7-99P	C	P-value = 0.001 when genotyped individually in the test sample (NIMH); P-value = 0.542 when individually genotyped in the Replication sample (German); P-value = 0.533 in the combined dataset. OR (95% CI)=NS		Negative
rs7212506	ABCA6	C	P-value = 0.236 when genotyped individually in the test sample (NIMH)		Negative
rs7610043	RBMS3	G	P-value = 0.0008 when genotyped individually in the test sample (NIMH); P-value = 0.124 when individually genotyped in the Replication sample (German); P-value = 0.001 in the combined dataset. OR (95% CI)=1.21 (1.08-1.35)		Negative
rs2162126	PHF17	G	P-value = 0.004 when genotyped individually in the test sample (NIMH); P-value = 0.5516 when individually genotyped in the Replication sample (German); P-value = 0.21 in the combined dataset. OR (95% CI)=NS		Negative
rs2255317	RPL30 MATN2	G	P-value = 0.095 when genotyped individually in the test sample (NIMH)		Negative
rs2291182	CABS1	G	P-value = 0.011 when genotyped individually in the test sample (NIMH); P-value = 0.436 when individually genotyped in the Replication sample (German); P-value = 0.027 in the combined dataset. OR (95% CI)=1.25 (1.02-1.52)		Negative
rs2360111	NXN	G	P-value = 0.0007 when genotyped individually in the test sample (NIMH); P-value = 0.048 when individually genotyped in the Replication sample (German); P-value = 0.0003 in the combined dataset. OR (95% CI)=1.23 (1.10-1.37)		Negative
rs335929	AQP4 AQP4-AS1	C	P-value = 0.01 when genotyped individually in the test sample (NIMH); P-value = 0.097 when individually genotyped in the Replication sample (German); P-value = 0.004 in the combined dataset. OR (95% CI)=1.23 (1.07-1.41)		Negative
rs3736456	CYP4V2	C	P-value = 0.231 when genotyped individually in the test sample (NIMH)		Negative
rs3762685	PLSCR4	G	P-value = 7.50E-05 when genotyped individually in the test sample (NIMH); P-value = 0.293 when individually genotyped in the Replication sample (German); P-value = 0.0009 in the combined dataset. OR (95% CI)=1.22 (1.08-1.36)		Trend
rs4148776	ABCB11	C	P-value = 0.049 when genotyped individually in the test sample (NIMH); P-value = 0.418 when individually genotyped in the Replication sample (German); P-value = 0.062 in the combined dataset. OR (95% CI)=NS		Negative
rs7683874	SORCS2	G	P-value = 0.041 when genotyped individually in the test sample (NIMH); P-value = 0.006 when individually genotyped in the Replication sample (German); P-value = 0.0006 in the combined dataset. OR (95% CI)=1.51 (1.19-1.92)	significant at the P < 0.05 level in both samples. significant at the P < 0.05 level in both samples.	Negative
rs7660807	AMTN	G	P-value = 0.001 when genotyped individually in the test sample (NIMH); P-value = 0.266 when individually genotyped in the Replication sample (German); P-value = 0.004 in the combined dataset. OR (95% CI)=1.33 (1.10-1.61)		Negative
rs7933829	C11orf44	C	P-value = 0.002 when genotyped individually in the test sample (NIMH); P-value = 0.538 when individually genotyped in the Replication sample (German); P-value = 0.023 in the combined dataset. OR (95% CI)=1.18 (1.03-1.33)		Negative
rs7812884	CSMD1	A	P-value = 0.174 when genotyped individually in the test sample (NIMH)		Negative
rs942518	DFNB31	G	P-value = 0.035 when genotyped individually in the test sample (NIMH); P-value = 0.001 when individually genotyped in the Replication sample (German); P-value = 0.0001 in the combined dataset. OR (95% CI)=1.44 (1.20-1.74)		Negative
rs9315885	DGKH MAPK6PS3	T	P-value = 0.005 when genotyped individually in the test sample (NIMH); P-value = 0.006 when individually genotyped in the Replication sample (German); P-value = 0.0001 in the combined dataset. OR (95% CI)=1.26 (1.12-1.42)	significant at the P < 0.05 level in both samples. significant at the P < 0.05 level in both samples.	Negative
rs9863764	GRM7	G	P-value = 0.137 when genotyped individually in the test sample (NIMH)		Negative
rs9513877	NALCN	G	P-value = 0.0005 when genotyped individually in the test sample (NIMH); P-value = 0.021 when individually genotyped in the Replication sample (German); P-value = 8.10E-05 in the combined dataset. OR (95% CI)=1.26 (1.12-1.41)		Trend