Poster C12, Wednesday, August 21, 2019, 10:45 am – 12:30 pm, Restaurant Hall
Candidate genes for phonological processing disorders: A systematic review and expression analysis in Broca's and Wernicke's region
Nina Unger1,2,3, Stefan Heim2,4,5, Dominique Hilger2, Sebastian Bludau2, Peter Pieperhoff2, Sven Cichon2,6,7, Katrin Amunts1,2,5, Thomas W. Mühleisen2,1,6;1Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich-Heine-University Düsseldorf, 2Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, 3Department of Neurology, Medical Faculty, Uniklinik RWTH Aachen, 4Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, Uniklinik RWTH Aachen, 5JARA-Brain, Jülich-Aachen Research Alliance, 6Department of Biomedicine, University of Basel, 7Institute of Medical Genetics and Pathology, University Hospital Basel
Introduction: Disorders of phonological processing occur in dyslexia (DysL), dyscalculia (DysC), specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA). There is evidence that these disorders may have a common biological basis. However, it is not understood, which genetic factors are involved. To identify such factors, we performed a literature screening of the four disorders and sought for potentially overlapping candidate genes for phonological processing ("phonology genes"). Next, we statistically investigated expression profiles of these genes in the cortical areas of Broca's and Wernicke's region, the major language-related brain regions using an in-house software tool. We hypothesized that genes differentially expressed in Broca's and Wernicke's region are promising functional candidate genes for phonology. Methods: The PubMed screening included genetic linkage and association studies published between 2010 and 2018. A phonology gene had to be associated with at least two of the four disorders. Expression differences were tested in six left brain hemispheres using JuGEx that allows analysis of gene expression data from the Allen Human Brain Atlas in relation to cytoarchitectonic maps from the JuBrain Atlas (Bludau et al., 2018). Results: 43 studies were identified from which 13 candidate genes were selected for DysL/SLI, six for DysL/DysC, and two for DysL/DysC/SLI. The comparison between Broca's region (Amunts et al., 2004) and Wernicke's region (Morosan et al., 2005) showed a significantly higher expression in Broca's region for ATP2C2 (p=0.0451) and a significantly higher expression in Wernicke's region for DNAAF4 (p=0.0104); the remaining genes showed similar expression levels. Both genes showed significantly higher expression in the areal gray matter compared to brain white matter (p=0.0001). Discussion: Our literature analysis revealed 21 phonology genes for three of the investigated disorders. A reason that no gene overlapped with lvPPA could be that DysL/DysC/SLI are etiologically linked through impairments of phonological awareness and phonological working memory. lvPPA also shows an impaired phonological working memory; however, spontaneous speech and naming errors are primarily characterized by phonemic paraphasias (expressive symptom). Another reason could be that DysL/DysC/SLI show a strong neurodevelopmental component, while lvPPA is characterized by neurodegenerative processes in adulthood. Together with our expression analysis, two genes can be highlighted: ATP2C2 encodes a magnesium-dependent calcium transporter. Interestingly, low magnesium levels have been reported for DysL and other communication disorders. DNAAF4 is involved in nerve cell migration during neocortex development supporting the long-standing hypothesis of disturbed neuronal migration in DysL. Conclusions: The present study proposes new candidate genes for phonology. We assume that these genes do not only play a role for impaired phonological processing, but also for phonology in healthy individuals. The identified expression patterns may indicate functional specializations of the genes in Broca's and Wernicke's region. Evidence for their involvement in impaired phonological processing or phonology in the general population needs to be derived from large genetic association studies. To shed further light on the biological function of these genes, future studies should also examine whether they play a role in the development of Broca's and Wernicke's region in humans.
Themes: Language Genetics, Phonology and Phonological Working Memory
Method: Other