A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder

Strauss, Kevin A.; Markx, Sander; Georgi, Benjamin; Paul, Steven M.; Jinks, Robert N.; Hoshi, Toshinori; McDonald, Ann; First, Michael B.; Liu, Wen‐Cheng; Benkert, Abigail R.; Heaps, Adam D.; Tian, Yuan; Chakravarti, Aravinda; Bućan, Maja; Puffenberger, Erik G.

doi:10.1093/hmg/ddu335

Cited by 46 publications

(40 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found an elevated burden of risk variants in nicotinic acetylcholine receptors and CaM kinases. Others have reported variants in potassium channels and other gene sets (7,12). As larger sample sizes become available, it will be possible to conduct unbiased genome-wide analyses.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6)(7)(8)(9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

135

View full text Add to dashboard Cite

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A 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. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

135

View full text Add to dashboard Cite

show abstract

“…10–13 Two family studies 12,13 of the Amish population found evidence for partial segregation of a number of variants but little convergence on a specific gene or a linkage location. Similar results were found by Collins et al, 10 who performed exome sequencing of a large pedigree without conclusively identifying variants of large effect, and by Cruceanu et al, 11 who studied 25 pedigrees with lithium-responsive BD and also found limited evidence for cosegregation at the level of variants or genes across families.…”

mentioning

confidence: 99%

Exome Sequencing of Familial Bipolar Disorder

Goes¹,

Pirooznia²,

Parla

et al. 2016

JAMA Psychiatry

View full text Add to dashboard Cite

IMPORTANCE Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing. OBJECTIVE To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis. DESIGN, SETTING, AND PARTICIPANTS We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls. MAIN OUTCOMES AND MEASURES We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets. RESULTS We found 84 rare (frequency <1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected, P = .0066) and schizophrenia (11 observed vs. 5.1 expected, P = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected, P = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs 2.6 expected, P = .028). CONCLUSIONS AND RELEVANCE Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.

show abstract

“…This work was pioneered by Egeland and colleagues in the late 20 th century (Egeland et al 1989;Egeland1983). Ongoing studies are now being pursued by several groups (Yang et al 2009;Egeland et al 2012;Hou et al 2013;Ginns et al 2014;Strauss et al 2014;Georgi et al 2014;Kember et al 2015;Byrne et al 2015).…”

Section: Psychiatric Disordersmentioning

confidence: 99%

“…Additional challenges arise from limited sample sizes and strong local population structures. For example, a recent study identified a missense mutation in the KCNH7 gene among Old Order Amish in Pennsylvania, some of whom suffered from bipolar or other mood disorders (Strauss et al 2014). In vitro functional studies seemed to demonstrate a clear impact of the variant on HERG3 channels, but small sample size and lack of matched controls hampered the establishment of a significant association with the disorder.…”

Section: Psychiatric Disordersmentioning

confidence: 99%

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Lopes¹,

Hou²,

Boldt³

et al. 2016

Human Biology

View full text Add to dashboard Cite

Large-scale genotyping and next generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking to find genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

show abstract

A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder

Cited by 46 publications

References 40 publications

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Exome Sequencing of Familial Bipolar Disorder

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Contact Info

Product

Resources

About