Interaction effect between handedness and CNTNAP2 polymorphism (rs7794745 genotype) on voice-specific frontotemporal activity in healthy individuals: an fMRI study

Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.

[1]  N. Yahata,et al.  Language Processing and Human Voice Perception in Schizophrenia: A Functional Magnetic Resonance Imaging Study , 2006, Biological Psychiatry.

[2]  K. Lunetta,et al.  Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families , 2011, Neurobiology of Aging.

[3]  Stephen M. Rao,et al.  Human Brain Language Areas Identified by Functional Magnetic Resonance Imaging , 1997, The Journal of Neuroscience.

[4]  H. Tanaka,et al.  Neural Responses to Human Voice and Hemisphere Dominance for Lexical-semantic Processing , 2007, Methods of Information in Medicine.

[5]  T. Auer,et al.  White-matter microstructure and language lateralization in left-handers: A whole-brain MRI analysis , 2013, Brain and Cognition.

[6]  D. Geschwind,et al.  Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Gordon E. Pelton.  Voice processing , 1993 .

[8]  P. Hof,et al.  Analysis of synaptic gene expression in the neocortex of primates reveals evolutionary changes in glutamatergic neurotransmission. , 2015, Cerebral cortex.

[9]  Olga Peñagarikano,et al.  What does CNTNAP2 reveal about autism spectrum disorder? , 2012, Trends in molecular medicine.

[10]  Jessica A. Turner,et al.  Multifaceted genomic risk for brain function in schizophrenia , 2012, NeuroImage.

[11]  Inge-Marie Eigsti,et al.  The neural underpinnings of prosody in autism , 2012, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[12]  O. Güntürkün,et al.  FOXP2 variation modulates functional hemispheric asymmetries for speech perception , 2013, Brain and Language.

[13]  C. Chabris,et al.  Brain activation during semantic processing in autism spectrum disorders via functional magnetic resonance imaging , 2006, Brain and Cognition.

[14]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[15]  C. Arango,et al.  Autism Spectrum Disorder: Does Neuroimaging Support the DSM-5 Proposal for a Symptom Dyad? A Systematic Review of Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging Studies , 2011, Journal of Autism and Developmental Disorders.

[16]  Pascal Belin,et al.  Is voice processing species-specific in human auditory cortex? An fMRI study , 2004, NeuroImage.

[17]  E. Grigorenko.  Speaking genes or genes for speaking? Deciphering the genetics of speech and language. , 2009, Journal of child psychology and psychiatry, and allied disciplines.

[18]  Nouchine Hadjikhani,et al.  fMRI activation during a language task in adolescents with ASD , 2008, Journal of the International Neuropsychological Society.

[19]  Hidehiko Takahashi,et al.  Cerebral responses to vocal attractiveness and auditory hallucinations in schizophrenia: a functional MRI study , 2013, Front. Hum. Neurosci..

[20]  Clare Marx,et al.  Shining a light , 2015 .

[21]  Joshua C. Poore,et al.  BDNF polymorphism-dependent OFC and DLPFC plasticity differentially moderates implicit and explicit bias. , 2011, Cerebral cortex.

[22]  C. Price.  The anatomy of language: contributions from functional neuroimaging , 2000, Journal of anatomy.

[23]  Jorge Sepulcre,et al.  Evidence from intrinsic activity that asymmetry of the human brain is controlled by multiple factors , 2009, Proceedings of the National Academy of Sciences.

[24]  G. D. Pearlson,et al.  Genetic influences of cortical gray matter in language-related regions in healthy controls and schizophrenia , 2011, Schizophrenia Research.

[25]  David Cucurell,et al.  The effects of COMT (Val108/158Met) and DRD4 (SNP -521) dopamine genotypes on brain activations related to valence and magnitude of rewards. , 2010, Cerebral cortex.

[26]  Ralph-Axel Müller,et al.  Atypical lexicosemantic function of extrastriate cortex in autism spectrum disorder: Evidence from functional and effective connectivity , 2012, NeuroImage.

[27]  T. Hajek,et al.  Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis , 2012, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[28]  B. Casey,et al.  Variant brain‐derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder , 2010, Annals of the New York Academy of Sciences.

[29]  A. Chakravarti,et al.  Defining the Contribution of CNTNAP2 to Autism Susceptibility , 2013, PloS one.

[30]  E. T. Possing,et al.  Language lateralization in left-handed and ambidextrous people: fMRI data , 2002, Neurology.

[31]  G. Clowry,et al.  The Corticofugal Neuron-Associated Genes ROBO1, SRGAP1, and CTIP2 Exhibit an Anterior to Posterior Gradient of Expression in Early Fetal Human Neocortex Development , 2010, Cerebral cortex.

[32]  J. Kleinman,et al.  Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. , 2013, JAMA psychiatry.

[33]  Stephanie J. Forkel,et al.  Altered Integrity of Perisylvian Language Pathways in Schizophrenia: Relationship to Auditory Hallucinations , 2011, Biological Psychiatry.

[34]  Christopher W Bartlett,et al.  Defining the genetic architecture of human developmental language impairment. , 2012, Life sciences.

[35]  B. Franke,et al.  Do candidate genes discriminate patients with an autism spectrum disorder from those with attention deficit/hyperactivity disorder and is there an effect of lifetime substance use disorders? , 2010, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[36]  Peter Hagoort,et al.  Neural correlates of language comprehension in autism spectrum disorders: When language conflicts with world knowledge , 2011, Neuropsychologia.

[37]  Richard S. Frackowiak,et al.  Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2 , 2010, NeuroImage.

[38]  Jan Gläscher,et al.  Visualization of Group Inference Data in Functional Neuroimaging , 2009, Neuroinformatics.

[39]  Simon E Fisher,et al.  Decoding the genetics of speech and language , 2013, Current Opinion in Neurobiology.

[40]  Peter Hagoort,et al.  CNTNAP2 and Language Processing in Healthy Individuals as Measured with ERPs , 2012, PloS one.

[41]  A. Monaco,et al.  Genetic Advances in the Study of Speech and Language Disorders , 2010, Neuron.

[42]  J A Veltman,et al.  CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy , 2008, Molecular Psychiatry.

[43]  M. Stein,et al.  A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Is Associated with Increased Risk for Selective Mutism and Social Anxiety-Related Traits , 2011, Biological Psychiatry.

[44]  C. Walsh,et al.  Molecular approaches to brain asymmetry and handedness , 2006, Nature Reviews Neuroscience.

[45]  Stephen M. Kosslyn,et al.  Cerebral lateralization , 1993, Current Opinion in Neurobiology.

[46]  D. Rujescu,et al.  CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study. , 2013, Journal of psychiatric research.

[47]  G. Geffen,et al.  Handedness in twins: joint analysis of data from 35 samples. , 2006, Twin research and human genetics : the official journal of the International Society for Twin Studies.

[48]  Susumu Mori,et al.  Coupling diffusion imaging with histological and gene expression analysis to examine the dynamics of cortical areas across the fetal period of human brain development. , 2013, Cerebral cortex.

[49]  Jean-Baptiste Poline,et al.  Genetic Variants of FOXP2 and KIAA0319/TTRAP/THEM2 Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions , 2012, The Journal of Neuroscience.

[50]  J. Pujol,et al.  Cerebral lateralization of language in normal left-handed people studied by functional MRI , 1999, Neurology.

[51]  Shenton,et al.  CNTNAP 2 polymorphisms and structural brain connectivity : A diffusion-tensor imaging study , 2013 .

[52]  J. A. Frost,et al.  Language dominance in neurologically normal and epilepsy subjects , 1999 .

[53]  Anthony G Christodoulou,et al.  A quality control method for detecting and suppressing uncorrected residual motion in fMRI studies. , 2013, Magnetic resonance imaging.

[54]  Mert R. Sabuncu,et al.  A Surface-based Analysis of Language Lateralization and Cortical Asymmetry , 2013, Journal of Cognitive Neuroscience.

[55]  R. Zatorre,et al.  Voice-selective areas in human auditory cortex , 2000, Nature.

[56]  Pascal Belin,et al.  Cerebral Processing of Voice Gender Studied Using a Continuous Carryover fMRI Design , 2012, Cerebral cortex.

[57]  H. Tanaka,et al.  A functional MRI study: cerebral laterality for lexical-semantic processing and human voice perception. , 2006, AJNR. American journal of neuroradiology.

[58]  Heather C Whalley,et al.  Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[59]  Guoyin Feng,et al.  CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population , 2013, Psychiatry Research.

[60]  D. Geschwind,et al.  A functional genetic link between distinct developmental language disorders. , 2008, The New England journal of medicine.

[61]  J. Hart,et al.  Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. , 2003, Brain research. Cognitive brain research.

[62]  S. Ikegawa,et al.  Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers , 2011, Journal of Human Genetics.

[63]  Jingping Zhao,et al.  Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population , 2010, Psychiatric genetics.

[64]  D. Bishop,et al.  CNTNAP2 variants affect early language development in the general population , 2011, Genes, brain, and behavior.

[65]  S. Vernes,et al.  Shining a light on CNTNAP2: complex functions to complex disorders , 2013, European Journal of Human Genetics.

[66]  R W Cox,et al.  Language processing is strongly left lateralized in both sexes. Evidence from functional MRI. , 1999, Brain : a journal of neurology.

[67]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.