15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

Helbig, Ingo; Mefford, Heather C; Sharp, Andrew J.; Guipponi, Michel; Fichera, Marco; Franke, André; Muhle, Hiltrud; Kovel, Carolien G.F. de; Baker, Carl; Spiczak, Sarah von; Kron, Katherine L.; Steinich, Ines; Kleefuß-Lie, Ailing A.; Leu, Costin; Gaus, Verena; Schmitz, Bettina; Klein, Karl Martin; Reif, Philipp S.; Rosenow, Felix; Weber, Yvonne G.; Lerche, Holger; Zimprich, Fritz; Urak, L.; Fuchs, Karoline; Feucht, Martha; Genton, Pierre; Thomas, Pierre; Visscher, Frank; Haan, Gerrit-Jan de; Møller, Rikke S.; Hjalgrim, Helle; Luciano, Daniela; Wittig, Michael; Nothnagel, Michael; Elger, Christian E.; Nürnberg, Peter; Romano, Corrado; Malafosse, Alain; Koeleman, Bobby P. C.; Lindhout, Dick; Stephani, Ulrich; Schreiber, Stefan; Eichler, Evan E.; Sander, Thomas

doi:10.1038/ng.292

Cited by 512 publications

(484 citation statements)

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“…The rare 15q13.3 microdeletion is strongly associated with many neuropsychiatric conditions, including schizophrenia. [25][26][27] This deletion is recurrent and probably arises from non-allelic homologous recombination when two direct repeats misalign during meiosis. Two large direct repeats likely to be responsible include CHRNA7 and CHRFAM7A 71 (see Supplementary Figure 1a).…”

Section: Discussionmentioning

confidence: 99%

“…These deletions are very rare in the general population (B0.02%), but more common in schizophrenia, autism/developmental disorders and some forms of intellectual impairment (B0.2-0.3%) and even more common in idiopathic generalized epilepsy (B1.0%). [25][26][27][28] These B2-Mb microdeletions lead to the loss of CHRNA7 and five other genes (Supplementary Figure 1a), but smaller variants that show a similar range of phenotypes remove only CHRNA7 and one other gene. 29 These observations strongly implicate the CHRNA7 region in schizophrenia and other neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

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Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

et al. 2012

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There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the a7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P ¼ 0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P ¼ 0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

et al. 2012

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“…This subunit has important roles in brain development and neuron differentiation and migration (Gotti et al 2009;Taly et al 2009), and its chromosomal locus was associated in humans with developmental and neurological disorders (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). Despite the importance of the α7 nAChR subunit, its deficiency results in viable, anatomically normal α7-null mice (Orr-Urtreger et al 1997;Paylor et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The nAChRs have been implicated in complex diseases affecting the nervous system, including epilepsy, schizophrenia, developmental disorders, and aging-associated neurodegenerative diseases such as AD and PD (Freedman et al 2001;Steinlein et al 1995). Several recent genome-wide association studies identified genomic alterations in the human α7 nAChR subunit gene locus in patients with schizophrenia, bipolar disorder, autism, developmental delay, and seizures (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). α7 subunits can form homopentameric receptor channels, which are activated by acetylcholine (ACh) and blocked by α-bungarotoxin (αBgtx).…”

Section: Introductionmentioning

confidence: 99%

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

Kedmi

Orr-Urtreger

2010

AGE

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Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice.

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“…3 Follow-up studies have strongly associated 15q13.3 deletions with both DD/ID 4 and schizophrenia. 5 The reciprocal microduplications of 15q13.3, which are very common in the general population with an estimated frequency of 1 in 180, 6 have been more challenging to interpret, as they do not manifest the high penetrance of neuropsychiatric phenotypes seen in deletion cases. Van Bon et al 2 first reported four patients with cognitive impairment and psychiatric disorders coinciding with BP4 and BP5 duplications.…”

Section: Introductionmentioning

confidence: 99%

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

Soler‐Alfonso

Carvalho

et al. 2014

Eur J Hum Genet

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Although deletions of CHRNA7 have been associated with intellectual disability (ID), seizures and neuropsychiatric phenotypes, the pathogenicity of CHRNA7 duplications has been uncertain. We present the first report of CHRNA7 triplication. Three generations of a family affected with various neuropsychiatric phenotypes, including anxiety, bipolar disorder, developmental delay and ID, were studied with array comparative genomic hybridization (aCGH). High-resolution aCGH revealed a 650-kb triplication at chromosome 15q13.3 encompassing the CHRNA7 gene, which encodes the alpha7 subunit of the neuronal nicotinic acetylcholine receptor. A small duplication precedes the triplication at the proximal breakpoint junction, and analysis of the breakpoint indicates that the triplicated segment is in an inverted orientation with respect to the duplication. CHRNA7 triplication appears to occur by a replication-based mechanism that produces inverted triplications embedded within duplications. Co-segregation of the CHRNA7 triplication with neuropsychiatric and cognitive phenotypes provides further evidence for dosage sensitivity of CHRNA7.

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15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

Cited by 512 publications

References 13 publications

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

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