BDgene

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

Search Gene with Disease Search Gene1 with Disease

Study Report

Comment on Study

View All Comments on Study

Basic Info

Reference	Ament, S. A., 2015 PMID: 25730879
Citation	Ament, S. A., et al. (2015). "Rare variants in neuronal excitability genes influence risk for bipolar disorder." Proc Natl Acad Sci U S A 112(11): 3576-3581.
Disease Type	Bipolar Disorder
Study Design	pedigree and case-control
Study Type	candidate-gene association study
Sample Size	41 BD pedigrees for whole-genome sequencing and analysis, 3,014 BD type 1 cases and 1,717 neurologically cleared controls for target sequencing
SNP/Region/Marker Size	3,087 candidate genes
Predominant Ethnicity	NIMH sample, and European-American ancestry
Population	Pedigrees collected by the National Institute of Mental Health (NIMH) Genetics Initiative and by sites at the University of California, San Diego; the University of California, San Francisco; and the University of Chicago. Population controls were drawn from a collection of >1,200 genomes in an in-house collection at the Institute for Systems Biology (Seattle, WA). Case-control samples were primarily from the GAIN and TGEN collections and also included 169 BD cases from a new prospective sample of lithium responsiveness in BD.

Detail Info

Sample Status	The sample for whole-genome sequencing has been described previously. Samples for target sequencing were primarily from the GAIN and TGEN collections and also included 169 BD cases from a new prospective sample of lithium responsiveness in BD.
Technique	Whole-Genome Sequencing and Targeted Sequencing
Statistical Method	Whole-genome sequencing was performed to >40Ã— coverage by Complete Genomics. SNVs, insertions, and deletions were called with the Complete Genomics analysis pipeline version 2.0 or 2.2, relative to the human reference genome GRCh37. We annotated variants to RefSeq gene models with Ingenuity Variant Analysis (Qiagen). We used additional annotations from the Family Genomics Workflow, including allele frequency estimates from Kaviar. Linear mixed modeling of single variant associations was implemented with EMMAX. Associations of genes and pathways with BD were calculated by comparing the frequency of fully and nearly fully segregating variants in BD pedigrees to an empirical distribution in control pedigrees. Sequence reads were aligned to the human reference genome (GRCh37) using Burrows-Wheeler Alignment, followed by indel realignment with the Genome Analysis Toolkit. We used SNVer to call SNVs in each pool and to estimate per-pool allele frequencies. Allele counts of low-frequency variants were normalized to adjust for stochastic variation in read depth. Statistical associations between the rare variants in each gene and BD affection status were assessed with the SKAT and C-alpha. We report empirical P values from 100,000 resampling permutations.
Result Summary	BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.

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

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs3811993	GABRA6			P-value=3.0e-5; q=8.9e-2	The top associated SNV was a missense SNV. The top associated SNV was a missense SNV.	Positive
rs147825070	GPR123			P-value=4.3e-5; q=8.9e-2	One of significant SNVs was a noncoding SNV in the 5' UTR of...... One of significant SNVs was a noncoding SNV in the 5' UTR of GPR123. More...	Positive

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

Gene	Statistical Values/Author Comments	Result Category
CACNG2	Regulatory P-value=0.00047, q-value=0.0041. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
CAMK2A	Coding P-value=0.22, q-value=0.48, Regulatory P-value=0.0014, q-value=0.0086. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
CACNA1C	Coding P-value=0.038, q-value=0.22, Regulatory P-value<1.0e-5, q-value=0.00026. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
CACNA1B	Regulatory P-value=0.00043, q-value=0.0041. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
GABRA4	P-value=0.0011, OR=14.9. No individual gene had a significant burden of segregating rare variants in BD pedigrees after corre...... No individual gene had a significant burden of segregating rare variants in BD pedigrees after correcting for multiple tests, although several genes had suggestive trends. More...	Positive
TFAM	P-value=0.0011, OR=14.9. No individual gene had a significant burden of segregating rare variants in BD pedigrees after corre...... No individual gene had a significant burden of segregating rare variants in BD pedigrees after correcting for multiple tests, although several genes had suggestive trends. More...	Positive
CACNA1D	Coding P-value=0.43, q-value=0.74, Regulatory P-value=0.0016, q-value=0.0086. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
NGF	Coding P-value=0.74, q-value=0.88, Regulatory P-value=0.0084, q-value=0.036. The gene has significant rare variant associations to BD. The gene has significant rare variant associations to BD.	Positive
GRIK2	P-value=0.011. No individual gene had a significant burden of segregating rare variants in BD pedigrees after corre...... No individual gene had a significant burden of segregating rare variants in BD pedigrees after correcting for multiple tests, although several genes had suggestive trends. More...	Positive
GFAP	P-value=0.0044, OR=11.8. No individual gene had a significant burden of segregating rare variants in BD pedigrees after corre...... No individual gene had a significant burden of segregating rare variants in BD pedigrees after correcting for multiple tests, although several genes had suggestive trends. More...	Positive
TPP1	P-value=0.0057. No individual gene had a significant burden of segregating rare variants in BD pedigrees after corre...... No individual gene had a significant burden of segregating rare variants in BD pedigrees after correcting for multiple tests, although several genes had suggestive trends. More...	Positive