Genome-Wide Linkage Analysis of Human Auditory Cortical Activation Suggests Distinct Loci on Chromosomes 2, 3, and 8

Neural processes are explored through macroscopic neuroimaging and microscopic molecular measures, but the two levels remain primarily detached. The identification of direct links between the levels would facilitate use of imaging signals as probes of genetic function and, vice versa, access to molecular correlates of imaging measures. Neuroimaging patterns have been mapped for a few isolated genes, chosen based on their connection with a clinical disorder. Here we propose an approach that allows an unrestricted discovery of the genetic basis of a neuroimaging phenotype in the normal human brain. The essential components are a subject population that is composed of relatives and selection of a neuroimaging phenotype that is reproducible within an individual and similar between relatives but markedly variable across a population. Our present combined magnetoencephalography and genome-wide linkage study in 212 healthy siblings demonstrates that auditory cortical activation strength is highly heritable and, specifically in the right hemisphere, regulated oligogenically with linkages to chromosomes 2q37, 3p12, and 8q24. The identified regions delimit as candidate genes TRAPPC9, operating in neuronal differentiation, and ROBO1, regulating projections of thalamocortical axons. Identification of normal genetic variation underlying neurophysiological phenotypes offers a non-invasive platform for an in-depth, concerted capitalization of molecular and neuroimaging levels in exploring neural function.

[1]  W. Walters,et al.  NIBP, a Novel NIK and IKKβ-binding Protein That Enhances NF-κB Activation* , 2005, Journal of Biological Chemistry.

[2]  Shaun Purcell,et al.  Powerful regression-based quantitative-trait linkage analysis of general pedigrees. , 2002, American journal of human genetics.

[3]  Rainer Goebel,et al.  Genetic Contribution to Variation in Cognitive Function: An fMRI Study in Twins , 2009, Science.

[4]  A Schnitzler,et al.  Native language, gender, and functional organization of the auditory cortex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  N. Kabani,et al.  Identification of genetically mediated cortical networks: a multivariate study of pediatric twins and siblings. , 2008, Cerebral cortex.

[6]  Michael F. Green,et al.  Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands , 2008, Biological Psychiatry.

[7]  S. Clarke,et al.  Cytochrome Oxidase, Acetylcholinesterase, and NADPH-Diaphorase Staining in Human Supratemporal and Insular Cortex: Evidence for Multiple Auditory Areas , 1997, NeuroImage.

[8]  R. Näätänen.  Implications of ERP data for psychological theories of attention , 1988, Biological Psychology.

[9]  M. Gazzaniga,et al.  Acetylcholinesterase staining in human auditory and language cortices: regional variation of structural features. , 1996, Cerebral cortex.

[10]  W. Walters,et al.  NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. , 2005, The Journal of biological chemistry.

[11]  Sarah E Medland,et al.  Genetic Variance in a Component of the Language Acquisition Device: ROBO1 Polymorphisms Associated with Phonological Buffer Deficits , 2011, Behavior genetics.

[12]  Andreas Meyer-Lindenberg,et al.  Imaging genetics of schizophrenia , 2010, Dialogues in clinical neuroscience.

[13]  Riitta Salmelin,et al.  Cortical differentiation of speech and nonspeech sounds at 100 ms: implications for dyslexia. , 2005, Cerebral cortex.

[14]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[15]  J. Eggermont.  On the rate of maturation of sensory evoked potentials. , 1988, Electroencephalography and clinical neurophysiology.

[16]  S. Makeig,et al.  Dopamine Effects on Human Error Processing Depend on Catechol-O-Methyltransferase VAL158MET Genotype , 2011, The Journal of Neuroscience.

[17]  Andreas Heinz,et al.  Catechol-O-Methyltransferase val158met Genotype Affects Processing of Emotional Stimuli in the Amygdala and Prefrontal Cortex , 2005, The Journal of Neuroscience.

[18]  I. Johnsrude,et al.  Spectral and temporal processing in human auditory cortex. , 2002, Cerebral cortex.

[19]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Hari.  The neuromagnetic method in the study of the human auditory cortex , 1990 .

[21]  P. Chauvel,et al.  Neuromagnetic source localization of auditory evoked fields and intracerebral evoked potentials: a comparison of data in the same patients , 2001, Clinical Neurophysiology.

[22]  R Hari,et al.  Neuromagnetic auditory evoked responses after a stroke in the right temporal lobe. , 1992, Neuroreport.

[23]  G. Abecasis,et al.  Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. , 2005, American journal of human genetics.

[24]  M. Reite,et al.  Magnetic auditory evoked fields: interhemispheric asymmetry. , 1981, Electroencephalography and clinical neurophysiology.

[25]  Juha Kere,et al.  The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia , 2005, PLoS genetics.

[26]  Jonas Obleser,et al.  Bilateral Speech Comprehension Reflects Differential Sensitivity to Spectral and Temporal Features , 2008, The Journal of Neuroscience.

[27]  Robin M. Murray,et al.  Heritability and Reliability of P300, P50 and Duration Mismatch Negativity , 2006, Behavior genetics.

[28]  Riitta Hari,et al.  Human ROBO1 Regulates Interaural Interaction in Auditory Pathways , 2012, The Journal of Neuroscience.

[29]  Marc Tessier-Lavigne,et al.  Roundabout Controls Axon Crossing of the CNS Midline and Defines a Novel Subfamily of Evolutionarily Conserved Guidance Receptors , 1998, Cell.

[30]  Heikki Lyytinen,et al.  Abnormal Auditory Cortical Activation in Dyslexia 100 msec after Speech Onset , 2002, Journal of Cognitive Neuroscience.

[31]  R. Freedman,et al.  Heritability of inhibitory gating of the P50 auditory-evoked potential in monozygotic and dizygotic twins. , 1996, Neuropsychobiology.

[32]  John S. Duncan,et al.  Hemispheric asymmetries in language-related pathways: A combined functional MRI and tractography study , 2006, NeuroImage.

[33]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[34]  Susumu Mori,et al.  Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain , 2006, Development.

[35]  D. Weinberger,et al.  Genetic variability of human brain size and cortical gyral patterns. , 1997, Brain : a journal of neurology.

[36]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[37]  W. Singer,et al.  Interhemispheric asymmetries of the modular structure in human temporal cortex. , 2000, Science.

[38]  P. Morosan,et al.  Probabilistic Mapping and Volume Measurement of Human Primary Auditory Cortex , 2001, NeuroImage.

[39]  C. Walsh,et al.  A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. , 2009, American journal of human genetics.

[40]  A. Noor,et al.  Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. , 2009, American journal of human genetics.

[41]  M. Hämäläinen,et al.  Effect of interaural time differences on middle-latency and late auditory evoked magnetic fields , 1994, Hearing Research.

[42]  N. Boutros,et al.  Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: A twin study , 2007, Schizophrenia Research.

[43]  R. Kahn,et al.  Quantitative genetic modeling of variation in human brain morphology. , 2001, Cerebral cortex.

[44]  Timothy E. J. Behrens,et al.  The evolution of the arcuate fasciculus revealed with comparative DTI , 2008, Nature Neuroscience.

[45]  V. Jousmäki,et al.  Automatic auditory discrimination is impaired in Parkinson's disease. , 1995, Electroencephalography and clinical neurophysiology.

[46]  A Pfefferbaum,et al.  Event-related potentials in schizophrenics. , 1980, Electroencephalography and clinical neurophysiology.

[47]  C. Schroeder,et al.  Speech-evoked activity in primary auditory cortex: effects of voice onset time. , 1994, Electroencephalography and clinical neurophysiology.

[48]  R. Oostenveld,et al.  Increased auditory cortical representation in musicians , 1998, Nature.

[49]  A. Galaburda,et al.  Cytoarchitectonic organization of the human auditory cortex , 1980, The Journal of comparative neurology.

[50]  D I Boomsma,et al.  Heritability of human brain functioning as assessed by electroencephalography. , 1996, American journal of human genetics.

[51]  R Näätänen,et al.  Replicability of MEG and EEG measures of the auditory N1/N1m-response. , 1998, Electroencephalography and clinical neurophysiology.

[52]  Tyrone D. Cannon,et al.  Genetic influences on brain structure , 2001, Nature Neuroscience.

[53]  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.