BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

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Study Report

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Basic Info

Reference	Strauss, K. A., 2014 PMID: 24986916
Citation	Strauss, K. A., et al. (2014). "A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder." Hum Mol Genet.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Genome-wide association study
Sample Size	26 Amish subjects from 4 families
SNP/Region/Marker Size	17609 exome variants
Predominant Ethnicity	Caucasian
Population	Amish
Gender	42% male and 58% female
Age Group	adult : mean=52, SD=11

Detail Info

Sample Diagnosis	DSM-IV-TR
Sample Status	Fourteen of 26 Amish subjects from Families A-D met DSM-IV-TR criteria for at least two of three symptom clusters (mania, depression or psychosis) and were designated as multidomain affected. They comprised diverse Axis 1 diagnoses: bipolar 1 with psychotic features (N=6), bipolar 2 with psychotic features (N=1), bipolar disorder not otherwise specified (N=3), schizoaffective disorder (N=2), schizophrenia with major depressive disorder (N=1), and recurrent major depression complicated by somatoform disorder and substance-induced psychosis (N=1).
Technique	Genotyped using the Illumina Omni 2.5 SNP array platform.
Statistical Method	Estimates of pair-wise relatedness of the 340 ASMAD subjects were obtained based on Illumina Omni 2.5 SNP array data. A x² statistic was used to assess distribution of 10 candidate alleles among individuals with and without mood disorders, and association of these variants with psychiatric diagnoses was tested using the FBAT and efficient mixed-model association expedited (EMMAX) methods. The Bonferroni correction was applied for multiple comparisons. FBAT P-values were -log10 transformed to construct.
Result Summary	KCNH7c.1181G >A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7c.1181G >A had the highest enrichment among individuals with bipolar spectrum disorder (x²=7.3) and the strongest family-based association with bipolar 1 (P=0.021), bipolar spectrum (P=0.031) and any major affective disorder (P=0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder.

SNPs reported by this study for BD (count: 9)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs34756139	NEK5	T/G		Bipolar 1 disorder: X²=0.1, FBAT P-value=0.349, EMMAX P-value=0.543; Bipolar spectrum disorder: X¹¹=0, FBAT P-value=0.722, EMMAX P-value=0.256	No significant associations were observed. No significant associations were observed.	Negative
rs3742290	NEK5 ALG11 UTP14C	A/G		Bipolar 1 disorder: X²=0.2, FBAT P-value=0.349, EMMAX P-value=0.543; Bipolar spectrum disorder: X¹⁰=0, FBAT P-value=0.722, EMMAX P-value=0.256	No significant associations were observed. No significant associations were observed.	Negative
rs2232386	KRT75	G/C		Bipolar 1 disorder: X²=0.8, FBAT P-value=0.405, EMMAX P-value=0.742; Bipolar spectrum disorder: X⁹=1.7, FBAT P-value=0.366, EMMAX P-value=0.555	No significant associations were observed. No significant associations were observed.	Negative
rs11542510	LETMD1 CSRNP2	G/A		Bipolar 1 disorder: X²=0.2, FBAT P-value=0.824, EMMAX P-value=0.939; Bipolar spectrum disorder: X⁸=0.1, FBAT P-value=0.654, EMMAX P-value=0.606	No significant associations were observed. No significant associations were observed.	Negative
rs117646559	CCDC65 FKBP11	G/T		Bipolar 1 disorder: X²=0.8, FBAT P-value=0.514, EMMAX P-value=0.637; Bipolar spectrum disorder: X⁷=0.1, FBAT P-value=0.751, EMMAX P-value=0.772	No significant associations were observed. No significant associations were observed.	Negative
rs61730283	ALG10B	A/G		Bipolar 1 disorder: X²=1.4, FBAT P-value=0.276, EMMAX P-value=0.194; Bipolar spectrum disorder: X⁶=0.9, FBAT P-value=0.599, EMMAX P-value=0.651	No significant associations were observed. No significant associations were observed.	Negative
rs75758327	XIRP2	G/C		Bipolar 1 disorder: X²=1.3, FBAT P-value=0.484, EMMAX P-value=0.465; Bipolar spectrum disorder: X⁴=2.6, FBAT P-value=0.408, EMMAX P-value=0.113	No significant associations were observed. No significant associations were observed.	Negative
rs78247304	KCNH7	C/T		Bipolar 1 disorder: X²=4.2, FBAT P-value=0.021, EMMAX P-value=0.174; Bipolar spectrum disorder: X³=7.3, FBAT P-value=0.031, EMMAX P-value=0.013	The only candidate allele shared among them was rs78247304, ...... The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7(c.1181G >A, p.Arg394His). More...	Positive
rs1143660	ALDH9A1	G/A		Bipolar 1 disorder: X²=0.4, FBAT P-value=0.408, EMMAX P-value=0.224; Bipolar spectrum disorder: X²=0.1, FBAT P-value=0.889, EMMAX P-value=0.303	No significant associations were observed. No significant associations were observed.	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
MUC4 Chr3:195492191 C/A	MUC4	missense	C/A		Bipolar 1 disorder: X²=0.8, FBAT P-value=0.965, EMMAX P-value=0.67; Bipolar spectrum disorder: X⁵=0.2, FBAT P-value=0.906, EMMAX P-value=0.356	No significant associations were observed. No significant associations were observed.	Negative

Genes reported by this study for BD (count: 10)

Gene	Statistical Values/Author Comments	Result Category
NEK5	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
MUC4	No significant association was observed between this variant and BD. No significant association was observed between this variant and BD.	Negative
ALG10B	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
XIRP2	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
KCNH7	This gene has the only candidate allele shared among them. This gene has the only candidate allele shared among them.	Positive
ALDH9A1	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
UTP14C	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
KRT75	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
CSRNP2	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative
CCDC65	The associated SNP in this gene showed no significant association with BD. The associated SNP in this gene showed no significant association with BD.	Negative