Study Report

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Basic Info

Reference	McQuillin, A., 2006 PMID: 16205735
Citation	McQuillin, A., N. J. Bass, et al. (2006). "Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3." Mol Psychiatry 11(2): 134-142.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Mutation study and candidate-gene association study
Sample Size	600 bipolar cases and 450 controls
SNP/Region/Marker Size	26 variants
Predominant Ethnicity	Caucasian
Population	Irish, Welsh, Scottish or English

Detail Info

Sample Diagnosis	Research Diagnostic Criteria
Sample Status	The cases were recruited from London NHS psychiatric services. All case and control subjects were interviewed using the Lifetime Version of the Schizophrenia and Affective Disorders Schedule (SADSL). This information was supplemented by material from case-notes.
Technique	genotyping using PCR
Statistical Method	Tests of allelic association that incorporated a Monte Carlo empirical test of significance, which does not need further correction for multiple alleles were carried out using CLUMP. Maximum likelihood estimates of haplotype frequencies were computed with GENECOUNTING and empirical tests of significance of haplotypic association, which do not need further correction for multiple haplotypes were computed with permutation tests.
Result Summary	We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.

SNPs reported by this study for BD (count: 11)

SNP	Related Gene(s)	Statistical Values	Author Comments	Result Category
rs36007753	TRPM2	no P-value	novel Polymorphisms identified in this study novel Polymorphisms identified in this study	Trend
rs35449326	C21orf90 TSPEAR	no P-value	novel Polymorphisms identified in this study novel Polymorphisms identified in this study	Trend
rs933151	TRPM2	P-value = 0.331, Pearson's X²=0.944		Negative
rs34214578	TRPM2	no P-value	novel Polymorphisms identified in this study novel Polymorphisms identified in this study	Trend
rs233283	KRTAP10-4 TSPEAR	P-value = 0.494, Pearson's X²=0.467		Negative
rs35288229	TRPM2	no P-value	novel Polymorphisms identified in this study novel Polymorphisms identified in this study	Trend
rs35028190	C21orf90 TSPEAR	no P-value	novel Polymorphisms identified in this study novel Polymorphisms identified in this study	Trend
rs1618355	TRPM2	P-value = 0.427, Pearson's X²=0.63		Negative
rs1556314	TRPM2	P-value = 0.008, Pearson's X²=7.039	showed allelic association with bipolar disorder showed allelic association with bipolar disorder	Positive
rs1785467	TRPM2	P-value = 0.025, Pearson's X²=5.057	showed allelic association with bipolar disorder showed allelic association with bipolar disorder	Positive
rs1785437	TRPM2	P-value = 0.28, Pearson's X²=1.17		Negative

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs1556314 - rs1785467 - D21S171		TRPM2	overall empirical significance P-value = 0.011	Using the asymptotic distribution, the test for haplotype as...... Using the asymptotic distribution, the test for haplotype association for the two associated SNPs and the associated microsatellite D21S171 of P=0.007. The empirical P-values using permutation tests was 0.011. More...	Positive
rs1556314 - rs1785467		TRPM2	overall empirical significance P-value = 0.010	Using the asymptotic distribution, the test for haplotype as...... Using the asymptotic distribution, the test for haplotype association for the two associated SNPs rs1556314 and rs1785467 was significant at P=0.009. The empirical P-values using permutation tests was P=0.01. More...	Positive

Other variants reported by this study for BD (count: 24)

Variant Name	Related Gene	Type	Statistical Values	Author Comments	Result Category
AGAT10		microsatellite	P-value = 0.36, Pearson's X²=8.766, P-value = 0.402, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=6.23, P-value = 0.163, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=4.94, P-value = 0.306, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=5.22	the microsatellite AGAT10 did not show significant allelic a...... the microsatellite AGAT10 did not show significant allelic association with the empirical test of significance implemented in CLUMP. However, when each allele was compared with the sum of the remaining alleles in a 2*2 contingency table, an uncorrected P-value of 0.026 was obtained. More...	Negative
D21S1260		microsatellite	P-value = 0.168, Pearson's X²=15.062, P-value = 0.072, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=14.19, P-value = 0.031, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=8.128, P-value = 0.389, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=6.333	Two microsatellites D21S171 and D21S1260 provided evidence f...... Two microsatellites D21S171 and D21S1260 provided evidence for association with bipolar disorder. D21S1260 also showed evidence for association with the CLUMP T3 statistic. More...	Positive
22A5.GT124		microsatellite	P-value = 0.273, Pearson's X²=6.399, P-value = 0.222, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=5.739, P-value = 0.604, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=1.715, P-value = 0.251, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=4.031		Negative
314n7CA23		microsatellite	P-value = 0.149, Pearson's X²=12.039, P-value = 0.837, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=2.92, P-value = 0.577, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=2.532, P-value = 0.477, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=4.244		Negative
D21S171		microsatellite	P-value = 0.057, Pearson's X²=19.767, P-value = 0.177, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=11.447, P-value = 0.016, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=8.953, P-value = 0.034, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=11.934	Two microsatellites D21S171 and D21S1260 provided evidence f...... Two microsatellites D21S171 and D21S1260 provided evidence for association with bipolar disorder. D21S171 was significant with empirical P-values of 0.016 and 0.034 with the T3 and T4 tests of CLUMP. More...	Positive
218C10.CA44		microsatellite	P-value = 0.607, Pearson's X²=2.751, P-value = 0.605, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=2.751, P-value = 0.5136, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=2.089, P-value = 0.505, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=2.402		Negative
ATTT11		microsatellite	P-value = 0.388, Pearson's X²=6.06, P-value = 0.464, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=4.71, P-value = 0.639, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=1.73, P-value = 0.39, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=3.57		Negative
C21ORF2		insertion/deletion	P-value = 0.923, Pearson's X²=0.246, P-value = 0.761, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=0.117, P-value = 0.779, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=0.135, P-value = 0.923, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=0.135		Negative
314n7CA28		microsatellite	P-value = 0.956, Pearson's X²=5.316, P-value = 0.977, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=3.061, P-value = 0.824, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=1.937, P-value = 0.983, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=1.937		Negative
314n7CT18		microsatellite	P-value = 0.526, Pearson's X²=19.165, P-value = 0.326, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=15.487, P-value = 0.118, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=6.594, P-value = 0.321, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=11.471		Negative
D21S1897		microsatellite	P-value = 0.22, Pearson's X²=11.988, P-value = 0.28, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=8.021, P-value = 0.2, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=4.343, P-value = 0.13, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=8.669		Negative
D21s1411		microsatellite	P-value = 0.453, Pearson's X²=15.051, P-value = 0.266, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=14.517, P-value = 0.116, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=6.705, P-value = 0.203, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=10.579		Negative
COL6A1		VNTR	P-value = 0.495, Pearson's X²=7.415, P-value = 0.476, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=5.357, P-value = 0.47, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=2.476, P-value = 0.479, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=4.072		Negative
rs458178			P-value = 0.818, Pearson's X²=0.053		Negative
CD18-AciI		microsatellite	P-value = 0.791, Pearson's X²=0.124		Negative
PCNT2-AluI		microsatellite	P-value = 0.788, Pearson's X²=0.096		Negative
D21S266		microsatellite	P-value = 0.189, Pearson's X²=13.465, P-value = 0.292, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=8.582, P-value = 0.268, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=3.861, P-value = 0.622, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=4.221		Negative
D21S212		microsatellite	P-value = 0.293, Pearson's X²=15.916, P-value = 0.603, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=9.097, P-value = 0.521, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=3.281, P-value = 0.556, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=6.5		Negative
D21S1903		microsatellite	P-value = 0.223, Pearson's X²=17.257, P-value = 0.138, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=16.795, P-value = 0.105, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=6.544, P-value = 0.053, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=14.191		Negative
TMEM1 microsatellite	TRAPPC10	microsatellite	P-value = 0.408, Pearson's X²=0.774		Negative
S100B-HaeIII		microsatellite	P-value = 0.393, Pearson's X²=0.73		Negative
PKNOX1		microsatellite	P-value = 0.351, Pearson's X²=9.885, P-value = 0.744, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=3.537, P-value = 0.741, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=1.621, P-value = 0.757, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=2.725		Negative
PFKL		microsatellite	P-value = 0.152, Pearson's X²=10.348, P-value = 0.179, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=10.348, P-value = 0.063, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=6.639, P-value = 0.097, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=7.851		Negative
White PolyT		microsatellite	P-value = 0.39, Pearson's X²=3.205, P-value = 0.351, The X² statistic of a table with rare alleles grouped together to prevent small expected cell counts=3.205, P-value = 0.423, The largest of the w2 statistics of 2 2 tables each of which compares one allele against the rest grouped together=2.32, P-value = 0.452, The largest of the X² statistics of all possible 2*2 tables comparing any combination of alleles against the rest=2.32		Negative