Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.
Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype.
Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany. Electronic address: maennel@cbs.mpg.de.
Claudia
C
Männel
Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Lars
L
Meyer
Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany.
Arndt
A
Wilcke
Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany; Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Johannes
J
Boltze
Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany; Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
Holger
H
Kirsten
Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Angela D
AD
Friederici
D000328:Adult; D001307:Auditory Perception / Q000502:physiology; D032882:Comprehension; D004410:Dyslexia / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D058068:Endophenotypes; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D007807:Language Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology; D008570:Memory, Short-Term; D010641:Phenotype; D011932:Reading; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D012306:Risk; D012677:Sensation / Q000502:physiology; D013702:Temporal Lobe / Q000473:pathology
D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human
Developmental dyslexia; Genetic risk; Gray matter; Posterior temporal cortex; Working memory