CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy

Friedman, Joseph I.; Vrijenhoek, Terry; Markx, Sander; Janssen, Irene M.; Vliet, Walter A van der; Faas, Brigitte H. W.; Knoers, Nine V A M; Cahn, Wiepke; Kahn, René S.; Edelmann, Lisa; Davis, Kenneth L.; Silverman, Jeremy M.; Brunner, Han G.; Kessel, A.H.M. Geurts van; Wijmenga, Cisca; Ophoff, Roel A.; Veltman, Joris A.

doi:10.1038/sj.mp.4002049

Cited by 268 publications

(193 citation statements)

References 36 publications

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…36,38 So far it has been suggested as a candidate gene for various neuropsychiatric disorders, [39][40][41][42][43][44][45] however little is known about its specific function and regulation. This protein contains multiple interaction domains such as laminin G, fibrinogen-like domains and epidermal growth factor (EGF)-repeat domains that are also found in members of the fibrillins and fibulins protein families.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

et al. 2010

View full text Add to dashboard Cite

Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P c ¼0.0108, rs2141388: P c ¼0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

et al. 2010

View full text Add to dashboard Cite

show abstract

“…2 This chromosomal translocation likely disrupted the normal expression of genes located elsewhere in the genome. Since then, other patients have been identified with chromosomal rearrangements affecting multiple genes including CNTNAP2, which are likely to confound the effects resulting from CNTNAP2 mutation [3][4][5][6][7][8][9] (Table 1). However, patients carrying point mutations or microdeletions that affect only the CNTNAP2 locus have now been reported, which provides insight into the deficit caused specifically by reduction or loss of CNTNAP2; [10][11][12][13][14][15][16] (Table 1).…”

Section: Cntnap2 and Cognitive Disorders Mutations Of Cntnap2mentioning

confidence: 99%

“…5,18,19 An intron 3 deletion containing no known functional elements was identified in a schizophrenia patient who presented with seizures, but normal language. 5 A deletion within intron 1 was reported in two independent patients suffering from ASD, ID and dysarthric language 18 and from ADHD, 19 respectively. Intron 1 contains a regulatory element bound by the FOXP2 transcription factor.…”

Section: Cntnap2 and Cognitive Disorders Mutations Of Cntnap2mentioning

confidence: 99%

Shining a light on CNTNAP2: complex functions to complex disorders

2013

View full text Add to dashboard Cite

The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

show abstract

“…Alternative genome-wide molecular genetic approaches, such as array-based association and copy number variation (CNV) analyses, 8 have recently been used to identify genomic aberrations underlying several neuropsychiatric disorders, including mental retardation (for review see Stankiewicz and Beaudet 9 ), autism, 10-12 schizophrenia [13][14][15][16][17][18][19] and ADHD. 20 These CNV analyses have inherent drawbacks and novel technical, statistical and epidemiological methods are required to identify disease risk genes in a reliable way.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

View full text Add to dashboard Cite

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domaincontaining protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 a subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a B3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

show abstract

CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy

Cited by 268 publications

References 36 publications

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

Shining a light on CNTNAP2: complex functions to complex disorders

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Contact Info

Product

Resources

About