Genetic variation in <i>CNTNAP2</i> alters brain function during linguistic processing in healthy individuals

Whalley, Heather C.; O’Connell, Garret; Sussmann, Jessika E.; Peel, Anna; Stanfield, Andrew C.; Hayiou‐Thomas, Marianna E.; Johnstone, Eve C.; Lawrie, Stephen M.; McIntosh, Andrew M.; Hall, Jérémy

doi:10.1002/ajmg.b.31241

Cited by 103 publications

(104 citation statements)

References 38 publications

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“…One study in (Ross et al, 1999) suggested decreased PLA2 activity in putamen for schizophrenia patients. It was also shown in (Whalley et al, 2011) that the association between CNTNAP2 gene and brain activity exists in the right inferior frontal gyrus in healthy individuals during a language task, which may indicate the potential risk to mental illness.…”

Section: Biological Implicationsmentioning

confidence: 94%

Joint sparse canonical correlation analysis for detecting differential imaging genetics modules

et al. 2016

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Motivation: Imaging genetics combines brain imaging and genetic information to identify the relationships between genetic variants and brain activities. When the data samples belong to different classes (e.g. disease status), the relationships may exhibit class-specific patterns that can be used to facilitate the understanding of a disease. Conventional approaches often perform separate analysis on each class and report the differences, but ignore important shared patterns. Results: In this paper, we develop a multivariate method to analyze the differential dependency across multiple classes. We propose a joint sparse canonical correlation analysis method, which uses a generalized fused lasso penalty to jointly estimate multiple pairs of canonical vectors with both shared and class-specific patterns. Using a data fusion approach, the method is able to detect differentially correlated modules effectively and efficiently. The results from simulation studies demonstrate its higher accuracy in discovering both common and differential canonical correlations compared to conventional sparse CCA. Using a schizophrenia dataset with 92 cases and 116 controls including a single nucleotide polymorphism (SNP) array and functional magnetic resonance imaging data, the proposed method reveals a set of distinct SNP-voxel interaction modules for the schizophrenia patients, which are verified to be both statistically and biologically significant.

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Section: Biological Implicationsmentioning

confidence: 94%

Joint sparse canonical correlation analysis for detecting differential imaging genetics modules

et al. 2016

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“…Mice with a Caspr2 deletion show analogous behavioral defects and symptoms [142]. Interestingly, common variants of the CNTNAP2 gene in healthy individuals are associated with abnormal language processing and are a risk factor for autism [143]. Caspr2 antibodies act by disrupting axonal potassium currents.…”

Section: Anti-vgkc-complex Encephalitismentioning

confidence: 99%

Autoimmune Encephalitides

Younger¹

2017

WJNS

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Autoimmune encephalitis is a potentially severe disorder of the brain of diverse causes with a complex differential diagnosis. Recent advances in the past decade have led to the elucidation of new syndromes and biological markers transforming the approach to diagnosis and management of autoimmune encephalitis. Limbic encephalitis, the commonest form of autoimmune encephalitis, combines common presentations of cognitive, psychiatric, and epileptic disorders and has until recently been considered paraneoplastic or postinfectious in origin. The autoimmune encephalitides are clinically and histopathologically associated with serum and intrathecal antibodies to intracellular and surface neuronal antigens, and constituents of the limbic system neuropil. This has led to a reconsideration of a number of neuropsychiatric and neurocognitive disorders as having shared mechanisms of origin. This chapter reviews their historical background, clinical presentation, laboratory evaluation, histopathology, diagnosis and management. KeywordsAutoimmune, Encephalitis, Hashimoto, Encephalopathy Historical PerspectiveCorsellis and colleagues [1] coined the term limbic encephalitis (LE) in 1968, noting a relation to bronchial cancer in three patients in the sixth to eighth decade of life, and showing close clinicopathologic similarity to cases described by Brierley and colleagues [2] six years earlier. All three cases had subacute temporal lobe seizures, neuropsychiatric, and memory disturbances for two years before death. Postmortem examination showed inflammatory lesions in limbic grey matter sections of the brain, especially in medial temporal lobe structures of the uncus and amygdala nuclei, and hippocampal, cingulum and dentate gyri. Case 2 had an undifferentiated non-metastatic lung carcinoma removed six months after onset of neurological symptoms, while two others had a clinically unsus- The formulation of the relation of GAD antibodies to SPS has been especially instructive in understanding how far the science of autoimmune neurologic disorder has advanced. In 1988, Solimena and colleagues [28] investigated the existence of non-paraneoplastic CNS autoimmunity in a patient with SPS, epilepsy and type-1 diabetes (T1D), and increased titers of oligoclonal CSF IgG. Both the serum and CSF produced identical intense staining of all gray-matter regions. GAD65 was thence an important autoantigen in T1D, being highly expressed in the cytoplasm of pancreatic β cells. GAD-derived peptides were presentable by main histocompatibility complex (MHC) class I molecules and recognized by CD8+ cells on the surface of β cells [29]. Activation of CD8+ GAD-specific T-cells further differentiated into memory cells suggesting a pathogenic role in T1D [30]. However, only patients with very high titers of GAD were associated with LE [31], and they typically presented with recent-onset temporal lobe epilepsy (TLE) and intrathecal secretion, defining a form of non-paraneoplastic LE. Other patients within the SPS spectrum harbored antibodies agains...

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“…Moreover, it has become clear that, just as observed for other measures of cognition and behavior, the effect sizes of common genomic variants are small and require large samples to achieve sufficient power (Thompson et al 2014). Imaging genetic studies of language are beginning to be performed, with intriguing results; again, to take the example of CNTNAP2, common variants of this gene are reported to be associated with language-related brain activations (Whalley et al 2011), event-related potentials (Kos et al 2012), and altered structural connectivity (Dennis et al 2011) in the healthy brain. However, note that most studies in this area have used small sample sizes, yielding low power and high risk of type I error (false-positive findings).…”

Section: Universality Variability and The Era Of Personal Genomicsmentioning

confidence: 99%

Genetics and the Language Sciences

Fisher

Vernes

2015

Annu. Rev. Linguist.

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Theories addressing the biological basis of language must be built on an appreciation of the ways that molecular and neurobiological substrates can contribute to aspects of human cognition. Here, we lay out the principles by which a genome could potentially encode the necessary information to produce a language-ready brain. We describe what genes are; how they are regulated; and how they affect the formation, function, and plasticity of neuronal circuits. At each step, we give examples of molecules implicated in pathways that are important for speech and language. Finally, we discuss technological advances in genomics that are revealing considerable genotypic variation in the human population, from rare mutations to common polymorphisms, with the potential to relate this variation to natural variability in speech and language skills. Moving forward, an interdisciplinary approach to the language sciences, integrating genetics, neurobiology, psychology, and linguistics, will be essential for a complete understanding of our unique human capacities. 289

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Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals

Cited by 103 publications

References 38 publications

Joint sparse canonical correlation analysis for detecting differential imaging genetics modules

Joint sparse canonical correlation analysis for detecting differential imaging genetics modules

Autoimmune Encephalitides

Genetics and the Language Sciences

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