Study Report

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Basic Info

Reference	Potash, J. B., 2008 PMID: 17671966
Citation	Potash, J. B., S. Buervenich, et al. (2008). "Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1." Am J Med Genet B Neuropsychiatr Genet 147B(1): 59-67.
Disease Type	Bipolar Disorder
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	305 families encompassing 506 parents and 529 affected probands and siblings. 305 cases and 329 controls for case-control association analyses
SNP/Region/Marker Size	189 SNPs
Predominant Ethnicity	Caucasian
Population	Subjects were drawn from the NIMH Genetics Initiative waves I and II samples, the Johns Hopkins sample, and the Clinical Neurogenetics sample.

Detail Info

Sample Diagnosis	DSM-IV; DSM-III-R; Diagnostic Interview for Genetic Studies (DIGS)
Technique	SNP genotyping was performed by Illumina using their BeadArray platform
Statistical Method	Haploview was employed to measure LD by r². Family-based association testing was carried out with FBAT, the GENASSOC program was used to determine family-based genotypic relative risks and odds ratios. The TDTphase component of the UNPHASED package was used to calculate allelic odds ratios. Case-control association testing was performed (using the proband from each family as a case) with the COCAPHASE component of the UNPHASED package. The EM algorithm was used to provide maximum-likelihood estimates of haplotype frequencies.
Result Summary	A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P=0.0011) and with psychotic BPAD (allele-wise P=0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotypewise results for rs2413338 in HMG2L1 showed an empirical P=0.037 for the difference between subsets.

SNPs reported by this study for BD (count: 24)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs138773	TOM1	C/G	Family-based P-value = 0.04 for all BPAD subjects, family-based P-value = 0.009 for BPAD subjects with psychotic symptoms, family-based P-value = 0.03 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.0076 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.18 for all BPAD subjects, case-control P-value = 0.19 for BPAD subjects with psychotic symptoms, case-control P-value = 0.064 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.15 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs138764	TOM1	T/C	Family-based P-value = 0.037 for all BPAD subjects, family-based P-value = 0.017 for BPAD subjects with psychotic symptoms, family-based P-value = 0.043 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.013 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.17 for all BPAD subjects, case-control P-value = 0.21 for BPAD subjects with psychotic symptoms, case-control P-value = 0.14 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.19 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs138784	TOM1	A/G	Family-based P-value = 0.0048 for all BPAD subjects, family-based P-value = 0.002 for BPAD subjects with psychotic symptoms, family-based P-value = 0.021 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.0043 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.8 for all BPAD subjects, case-control P-value = 0.94 for BPAD subjects with psychotic symptoms, case-control P-value = 0.15 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.25 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock, the most significant result was for rs138784 within TOM1 More...	Positive
rs138781	TOM1	G/A	Family-based P-value = 0.047 for all BPAD subjects, family-based P-value = 0.013 for BPAD subjects with psychotic symptoms, family-based P-value = 0.0067 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.0033 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.13 for all BPAD subjects, case-control P-value = 0.14 for BPAD subjects with psychotic symptoms, case-control P-value = 0.056 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.15 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs137252		G/T	Family-based P-value = 0.01 for all BPAD subjects, family-based P-value = 0.025 for BPAD subjects with psychotic symptoms.Case-control P-value = 0.43 for all BPAD subjects, case-control P-value = 0.73 for BPAD subjects with psychotic symptoms.		Positive
rs11703672	TOM1	G/A	Family-based P-value = 0.042 for all BPAD subjects, family-based P-value = 0.1 for BPAD subjects with psychotic symptoms. Case-control P-value = 0.034 for all BPAD subjects, case-control P-value = 0.076 for BPAD subjects with psychotic symptoms.		Positive
rs2157221		T/G	Family-based P-value = 0.39 for all BPAD subjects, family-based P-value = 0.71 for BPAD subjects with psychotic symptoms. Case-control P-value = 0.25 for all BPAD subjects, case-control P-value = 0.11 for BPAD subjects with psychotic symptoms.		Negative
rs2157220		T/C	Family-based P-value = 0.36 for all BPAD subjects, family-based P-value = 0.61 for BPAD subjects with psychotic symptoms, family-based P-value = 0.075 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.11 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.69 for all BPAD subjects, case-control P-value = 0.33 for BPAD subjects with psychotic symptoms, case-control P-value = 0.29 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.13 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Negative
rs4462	TOM1	A/G	Family-based P-value = 0.037 for all BPAD subjects, family-based P-value = 0.013 for BPAD subjects with psychotic symptoms, family-based P-value = 0.038 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.011 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.17 for all BPAD subjects, case-control P-value = 0.19 for BPAD subjects with psychotic symptoms, case-control P-value = 0.16 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.19 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs2413338	HMGXB4	C/T	Family-based P-value = 0.046 for all BPAD subjects, family-based P-value = 0.01 for BPAD subjects with psychotic symptoms, family-based P-value = 0.045 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.012 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.15 for all BPAD subjects, case-control P-value = 0.12 for BPAD subjects with psychotic symptoms, case-control P-value = 0.35 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.27 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs2015181		A/G	Family-based P-value = 0.16 for all BPAD subjects, family-based P-value = 0.3 for BPAD subjects with psychotic symptoms, family-based P-value = 0.15 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.18 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.49 for all BPAD subjects, case-control P-value = 0.24 for BPAD subjects with psychotic symptoms, case-control P-value = 0.45 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.21 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Negative
rs1540300		G/C	Family-based P-value = 0.54 for all BPAD subjects, family-based P-value = 0.42 for BPAD subjects with psychotic symptoms, family-based P-value = 0.064 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.14 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.07 for all BPAD subjects, case-control P-value = 0.02 for BPAD subjects with psychotic symptoms, case-control P-value = 0.33 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.11 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Positive
rs2097368		A/G	Family-based P-value = 0.54 for all BPAD subjects, family-based P-value = 0.71 for BPAD subjects with psychotic symptoms, family-based P-value = 0.013 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.016 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.69 for all BPAD subjects, case-control P-value = 0.66 for BPAD subjects with psychotic symptoms, case-control P-value = 0.58 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.48 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Positive
rs2038010	HMGXB4	G/A	Family-based P-value = 0.041 for all BPAD subjects, family-based P-value = 0.015 for BPAD subjects with psychotic symptoms, family-based P-value = 0.045 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.018 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.17 for all BPAD subjects, case-control P-value = 0.19 for BPAD subjects with psychotic symptoms, case-control P-value = 0.17 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.19 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs713770	HMGXB4	A/G	Family-based P-value = 0.049 for all BPAD subjects, family-based P-value = 0.018 for BPAD subjects with psychotic symptoms, family-based P-value = 0.047 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.015 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.17 for all BPAD subjects, case-control P-value = 0.19 for BPAD subjects with psychotic symptoms, case-control P-value = 0.17 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.18 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs739015	TOM1	A/G	Family-based P-value = 0.13 for all BPAD subjects, family-based P-value = 0.073 for BPAD subjects with psychotic symptoms, family-based P-value = 0.16 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.14 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.017 for all BPAD subjects, case-control P-value = 0.032 for BPAD subjects with psychotic symptoms, case-control P-value = 0.89 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.27 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Positive
rs743810	TOM1	A/C	Family-based P-value = 0.42 for all BPAD subjects, family-based P-value = 0.43 for BPAD subjects with psychotic symptoms, family-based P-value = 0.047 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.12 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.91 for all BPAD subjects, case-control P-value = 0.74 for BPAD subjects with psychotic symptoms, case-control P-value = 0.32 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.25 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Positive
rs762967	TOM1	A/G	Family-based P-value = 0.12 for all BPAD subjects, family-based P-value = 0.15 for BPAD subjects with psychotic symptoms, family-based P-value = 0.1 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.12 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.59 for all BPAD subjects, case-control P-value = 0.87 for BPAD subjects with psychotic symptoms, case-control P-value = 0.24 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.4 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Negative
rs4465	TOM1	G/A	Family-based P-value = 0.03 for all BPAD subjects, family-based P-value = 0.009 for BPAD subjects with psychotic symptoms, family-based P-value = 0.0067 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.0033 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.14 for all BPAD subjects, case-control P-value = 0.16 for BPAD subjects with psychotic symptoms, case-control P-value = 0.073 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.15 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs4467	TOM1 MIR3909	C/T	Family-based P-value = 0.85 for all BPAD subjects, family-based P-value = 10 for BPAD subjects with psychotic symptoms, family-based P-value = 0.15 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.13 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.68 for all BPAD subjects, case-control P-value = 0.75 for BPAD subjects with psychotic symptoms, case-control P-value = 0.51 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.94 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Negative
rs4511	TOM1	C/G	Family-based P-value = 0.0066 for all BPAD subjects, family-based P-value = 0.003 for BPAD subjects with psychotic symptoms, family-based P-value = 0.0013 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.00049 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.72 for all BPAD subjects, case-control P-value = 0.99 for BPAD subjects with psychotic symptoms, case-control P-value = 0.13 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.091 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs5750102	TOM1	G/A	Family-based P-value = 0.34 for all BPAD subjects, family-based P-value = 0.28 for BPAD subjects with psychotic symptoms, family-based P-value = 0.06 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.09 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.63 for all BPAD subjects, case-control P-value = 0.34 for BPAD subjects with psychotic symptoms, case-control P-value = 0.066 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.17 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).		Negative
rs932290	HMGXB4	G/A	Family-based P-value = 0.048 for all BPAD subjects, family-based P-value = 0.016 for BPAD subjects with psychotic symptoms, family-based P-value = 0.041 (3-marker sliding window with indicated marker first of the three), family-based P-value = 0.013 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).Case-control P-value = 0.17 for all BPAD subjects, case-control P-value = 0.17 for BPAD subjects with psychotic symptoms, case-control P-value = 0.17 (3-marker sliding window with indicated marker first of the three), case-control P-value = 0.18 (3-marker sliding window with indicated marker first of the three using only those BPAD subjects with psychotic symptoms).	The strongest signal in the family-based analysis emerged fr...... The strongest signal in the family-based analysis emerged from the 11 SNP HMG2L1/TOM1 haploblock. More...	Positive
rs9622182	TOM1	A/G	Family-based P-value = 0.71 for all BPAD subjects, family-based P-value = 0.12 for BPAD subjects with psychotic symptoms. Case-control P-value = 0.51 for all BPAD subjects, case-control P-value = 0.23 for BPAD subjects with psychotic symptoms.		Negative

Genes reported by this study for BD (count: 2)

Gene	Statistical Values/Author Comments	Result Category
HMGXB4	Permutation of genotypewise results for rs2413338 in HMG2L1 showed an empirical P=0.037 for the difference between subsets..	Positive
TOM1	A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P=0.0011) and with ps...... A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P=0.0011) and with psychotic BPAD (allele-wise P=0.00049). More...	Positive