Study Report

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Basic Info

Reference	Perlis, 2008 PMID: 18180429
Citation	Perlis, R. H., S. Purcell, et al. (2008). "Family-based association study of lithium-related and other candidate genes in bipolar disorder." Arch Gen Psychiatry 65(1): 53-61.
Disease Type	Bipolar I Disorder
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	379 parent-affected offspring trios
SNP/Region/Marker Size	1261 SNPs
Predominant Ethnicity	Caucasian
Population	NIMH collection

Detail Info

Sample Diagnosis	Diagnostic Interview for Genetic Studies
Technique	genotyping
Statistical Method	Primary analysis screened for association among the 379 BPI trios using the set-based test implemented in the PLINK association analysis toolset. The significance of these set statistics is then estimated by permutation, which allows a determination of genewise significance, allowing for correlation between SNPs and tests while controlling for type I error at the single-gene level. We chose to correct for testing multiple genes for association, within the constraints of available power, by setting a more stringent permuted genewise P .005 as the threshold for significance in the gene-based test.
Result Summary	No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, <.005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened.

SNPs reported by this study for BD (count: 30)

SNP	Related Gene(s)	Statistical Values	Result Category
rs10515827	GABRB2	Mean X²=8.1, P-value = 0.01 in gene-based association tests	Positive
rs1015101	DISC1	Mean X²=5.38, P-value = 0.03 in gene-based association tests	Positive
rs1011313	DTNBP1	Mean X²=3.08, P-value = 0.27 in gene-based association tests	Negative
rs1000117	DTNBP1	Mean X²=3.46, P-value = 0.38 in gene-based association tests	Negative
rs1934909	DISC1	Mean X²=4.86, P-value = 0.02 in gene-based association tests	Positive
rs16878388	NRG1	Mean X²=0.98, P-value = 0.51 in gene-based association tests	Negative
rs1644454	GABRB2	Mean X²=5.97, P-value = 0.003 in gene-based association tests	Positive
rs1554324	ST3GAL1	Mean X²=5.63, P-value = 0.003 in gene-based association tests	Positive
rs1481743	NRG1	Mean X²=1.15, P-value = 0.54 in gene-based association tests	Negative
rs11577215	DISC1	Mean X²=6.62, P-value = 0.08 in gene-based association tests	Negative
rs1106855	TACR1	Mean X²=5.14, P-value = 0.004 in gene-based association tests	Positive
rs10864702	DISC1	Mean X²=6.05, P-value = 0.04 in gene-based association tests	Positive
rs3758105	ST3GAL1	Mean X²=6.24, P-value = 0.005 in gene-based association tests	Positive
rs3771809	TACR1	Mean X²=7.63, P-value = 0.02 in gene-based association tests	Positive
rs2978012	ST3GAL1	Mean X²=6.82, P-value = 0.009 in gene-based association tests	Positive
rs3755456	TACR1	Mean X²=6.73, P-value = 0.009 in gene-based association tests	Positive
rs2466089	NRG1	Mean X²=1.43, P-value = 0.55 in gene-based association tests	Negative
rs2759346	DISC1 TSNAX	Mean X²=4.43, P-value = 0.01 in gene-based association tests	Positive
rs194073	GABRB2	Mean X²=6.75, P-value = 0.005 in gene-based association tests	Positive
rs1997679	DTNBP1	Mean X²=2.72, P-value = 0.21 in gene-based association tests	Negative
rs9296983	DTNBP1	Mean X²=2.36, P-value = 0.09 in gene-based association tests	Negative
rs9643297	ST3GAL1	Mean X²=7.61, P-value = 0.02 in gene-based association tests	Positive
rs760666	DTNBP1	Mean X²=2.5, P-value = 0.14 in gene-based association tests	Negative
rs7835464	ST3GAL1	Mean X²=9.06, P-value = 0.03 in gene-based association tests	Positive
rs4439987	TACR1	Mean X²=5.9, P-value = 0.005 in gene-based association tests	Positive
rs6546952	TACR1	Mean X²=10.14, P-value = 0.02 in gene-based association tests	Positive
rs3850733	GABRB2	Mean X²=8.19, P-value = 0.047 in gene-based association tests	Positive
rs3924999	NRG1	Mean X²=3.21, P-value = 0.41 in gene-based association tests	Negative
rs967771	GABRB2	Mean X²=7.33, P-value = 0.008 in gene-based association tests	Positive
rs967205	NRG1	Mean X²=1.97, P-value = 0.51 in gene-based association tests	Negative

Genes reported by this study for BD (count: 6)

Gene	Statistical Values/Author Comments	Result Category
TACR1	permuted P< .005 in gene-based association tests. No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. H...... No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and -aminobutyric acidA 2 receptor subunit (GABRB2) yielded evidence of association. More...	Positive
NRG1	permuted P> .005 in gene-based association tests.	Negative
ST3GAL1	permuted P< .005 in gene-based association tests. No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. H...... No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and -aminobutyric acidA 2 receptor subunit (GABRB2) yielded evidence of association. More...	Positive
DISC1	permuted P< .005 in gene-based association tests. Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, only D...... Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, only DISC1 showed evidence of association in this cohort. hese results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. More...	Positive
DTNBP1	permuted P> .005 in gene-based association tests.	Negative
GABRB2	permuted P< .005 in gene-based association tests. No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. H...... No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and -aminobutyric acidA 2 receptor subunit (GABRB2) yielded evidence of association. More...	Positive