Study Report

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Basic Info

Reference	Detera-Wadleigh, S. D., 2007 PMID: 17728666
Citation	Detera-Wadleigh, S. D., C. Y. Liu, et al. (2007). "Sequence variation in DOCK9 and heterogeneity in bipolar disorder." Psychiatr Genet 17(5): 274-286.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	Waves 1 and 2 (NIMH1-2): 153 families; Wave 3 (NIMH3): 221 families; Wave 4 (NIMH4): 275 families; CNG: 22 multiplex families; CHIP: 73 multiplex families
SNP/Region/Marker Size	98 SNPs
Predominant Ethnicity
Population	NIMH collections, CNG collections and CHIP collections
Gender	not mentioned
Age Group	not mentioned

Detail Info

Sample Diagnosis	DSM-IIIR and DSM-IV, Research Diagnostic Criteria
Sample Status	Family samples that were collected under the auspices of the National Institute of Mental Health (NIMH) Genetics Initiative for Bipolar Disorder, comprising the NIMH Waves 1-2, 3 and 4 were used in this study. Families were ascertained on the basis of a sibling pair affected with bipolar I (BPI) or schizoaffective-bipolar disorder (SA-BP).
Technique	genotyping with the Illumina Bead-Array assay, follow-up analysis of DOCK9 SNPs was genotyped by pyrosequencing or TaqMan allele discrimination assay
Statistical Method	Family-based association test was used to analyze genotype data from fine-scale mapping and to assess the effect of familial phenotype variables on association. TDTPHASE (UNPHASED package) was used for analysis of data from the initial screen with 98 SNPs, estimating odds ratios (ORs) and evaluation of transmission of parental alleles.
Result Summary	Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477-0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02-0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators. These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. They found evidence for the effect of phenotypic heterogeneity on association.

SNPs reported by this study for BD (count: 39)

SNP	Related Gene(s)	Statistical Values	Author Comments	Result Category
rs10492574	DOCK9	FBAT-e P-value = 0.0315 in NIMH1-2, FBAT-e P-value = 0.0604 in NIMH3, FBAT-e P-value = 0.1525 in NIMH4; FBAT-e P-value = 0.1202 (0.0595) in CHIP-CNG sample	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 More...	Positive
rs1041093	DOCK9	FBAT-e P-value = 0.0943 in NIMH1-2, FBAT-e P-value = 0.1103 in NIMH3, FBAT-e P-value = 0.3374 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1028910	DOCK9	TDT P-value = 0.408 in initial families	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1886554	DOCK9	FBAT-e P-value = 0.0156 in NIMH1-2, FBAT-e P-value = 0.0872 in NIMH3, FBAT-e P-value = 0.37 in NIMH4	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 More...	Positive
rs1886553	DOCK9	FBAT-e P-value = 0.1064 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1536657	DOCK9	FBAT-e P-value = 0.1799 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1359427	DOCK9	FBAT-e P-value = 0.1238 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1340	DOCK9 DOCK9-AS2	FBAT-e P-value = 0.0134 in NIMH1-2, FBAT-e P-value = 0.0396 in NIMH3, FBAT-e P-value = 0.4437 in NIMH4; FBAT-e P-value = 0.0683 in CHIP-CNG sample	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2; detected support for association in NIMH3 More...	Positive
rs1324982	DOCK9	FBAT-e P-value = 0.3152 in NIMH1-2, FBAT-e P-value = 0.7513 in NIMH3, FBAT-e P-value = 0.2899 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1299066	DOCK9	FBAT-e P-value = 0.5837 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs12428661	DOCK9	FBAT-e P-value = 1 in NIMH1-2, FBAT-e P-value = 0.2214 in NIMH3, FBAT-e P-value = 0.7988 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs772303	DOCK9	TDT P-value = 0.4886 in initial families	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs7334435	DOCK9	FBAT-e P-value = 0.0751 in NIMH1-2, FBAT-e P-value = 0.624 in NIMH3, FBAT-e P-value = 0.8361 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs7986477	DOCK9	FBAT-e P-value = 0.626 in NIMH1-2, FBAT-e P-value = 0.9359 in NIMH3, FBAT-e P-value = 0.8875 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs772311	DOCK9	FBAT-e P-value = 0.1535 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs874199	DOCK9	FBAT-e P-value = 0.3142 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs8002389	DOCK9	FBAT-e P-value = 0.2421 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs9517549	DOCK9 RNU6-83P	FBAT-e P-value = 0.0904 in NIMH1-2, FBAT-e P-value = 0.1871 in NIMH3, FBAT-e P-value = 0.66 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs9513550	DOCK9	FBAT-e P-value = 0.0222 in NIMH1-2	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 More...	Positive
rs9554547	DOCK9	FBAT-e P-value = 0.0601 in NIMH1-2, FBAT-e P-value = 0.4814 in NIMH3, FBAT-e P-value = 0.7677 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs9517575	DOCK9	FBAT-e P-value = 0.0078 in NIMH1-2, FBAT-e P-value = 0.0896 in NIMH3, FBAT-e P-value = 0.1673 in NIMH4; FBAT-e P-value = 0.0412 (0.0156) in CHIP-CNG sample	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 and in CHIP-CNG More...	Positive
rs9557137	DOCK9 DOCK9-AS2	FBAT-e P-value = 0.0071 in NIMH1-2, FBAT-e P-value = 0.0877 in NIMH3, FBAT-e P-value = 0.1038 in NIMH4	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 More...	Positive
rs9557134	DOCK9	FBAT-e P-value = 0.0064 in NIMH1-2, FBAT-e P-value = 0.0626 in NIMH3, FBAT-e P-value = 0.2271 in NIMH4; FBAT-e P-value = 0.0278 (0.0106) in CHIP-CNG sample	detected evidence of association at the P<0.05 level in the ...... detected evidence of association at the P<0.05 level in the NIMH1-2 and in CHIP-CNG More...	Positive
rs1887856	DOCK9 DOCK9-AS1	TDT P-value = 0.174 in initial families	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs1927568	DOCK9 DOCK9-AS2	TDT P-value = 0.00067 in initial families, FBAT-e P-value = 0.0119 in NIMH1-2, FBAT-e P-value = 0.1037 in NIMH3, FBAT-e P-value = 0.1372 in NIMH4	TDT analysis yielded evidence of association with bipolar di...... TDT analysis yielded evidence of association with bipolar disorder at rs1927568; detected evidence of association at the P<0.05 level in the NIMH1-2 More...	Positive
rs2000342	DOCK9 RNU6-83P	TDT P-value = 0.04766 in initial families, FBAT-e P-value = 0.1097 in NIMH1-2, FBAT-e P-value = 0.267 in NIMH3, FBAT-e P-value = 0.4405 in NIMH4	TDT analysis detected association with bipolar disorder TDT analysis detected association with bipolar disorder	Positive
rs2026024	DOCK9	TDT P-value = 0.2969 in initial families	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs2105425	DOCK9	FBAT-e P-value = 0.0578 in NIMH1-2, FBAT-e P-value = 0.7339 in NIMH3, FBAT-e P-value = 0.1788 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs2296983	DOCK9	FBAT-e P-value = 0.3029 in NIMH1-2, FBAT-e P-value = 0.3971 in NIMH3, FBAT-e P-value = 0.5306 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs2296994	DOCK9	FBAT-e P-value = 0.4778 in NIMH1-2, FBAT-e P-value = 0.2596 in NIMH3, FBAT-e P-value = 0.8132 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs2390129	DOCK9	TDT P-value = 0.01996 in initial families, FBAT-e P-value = 0.0558 in NIMH1-2	TDT analysis detected association with bipolar disorder TDT analysis detected association with bipolar disorder	Positive
rs2899	DOCK9	FBAT-e P-value = 0.3538 in NIMH1-2, FBAT-e P-value = 0.3402 in NIMH3, FBAT-e P-value = 0.1739 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs3858781	DOCK9	FBAT-e P-value = 0.0515 in NIMH1-2, FBAT-e P-value = 0.9758 in NIMH3, FBAT-e P-value = 0.4347 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs4772152	DOCK9	FBAT-e P-value = 0.7407 in NIMH1-2, FBAT-e P-value = 0.2866 in NIMH3, FBAT-e P-value = 0.1181 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs4772168	DOCK9	FBAT-e P-value = 0.1401 in NIMH1-2, FBAT-e P-value = 0.4855 in NIMH3, FBAT-e P-value = 0.5924 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs6491476	DOCK9	FBAT-e P-value = 0.1569 in NIMH1-2, FBAT-e P-value = 0.3669 in NIMH3, FBAT-e P-value = 0.4953 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs7328282	DOCK9	FBAT-e P-value = 0.6505 in NIMH1-2, FBAT-e P-value = 0.3679 in NIMH3, FBAT-e P-value = 0.1714 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs7331595	DOCK9 RPL7L1P12	FBAT-e P-value = 0.435 in NIMH1-2	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative
rs7333687	DOCK9 DOCK9-AS1	FBAT-e P-value = 0.352 in NIMH1-2, FBAT-e P-value = 0.8518 in NIMH3, FBAT-e P-value = 0.3033 in NIMH4	no significant over-transmission of any alleles was detected no significant over-transmission of any alleles was detected	Negative

Other variants reported by this study for BD (count: 1)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
DOCK9 (AAGTA) indel	DOCK9	insertion/deletion			FBAT-e P-value = 0.0087 in NIMH1-2, FBAT-e P-value = 0.1127 in NIMH3, FBAT-e P-value = 0.0817 in NIMH4	detected evidence of association at the P < 0.05 level in th...... detected evidence of association at the P < 0.05 level in the NIMH1-2 More...	Positive

Genes reported by this study for BD (count: 1)