Cognitive Genetics

Our research is focused on dyslexia, a severe disorder in the acquisition of reading and writing skills. The long-term objective is to develop an early test for dyslexia, allowing targeted support long before schooling starts.

50–70 percent of dyslexia can be explained by genetics. Hence our research is focused on the genetic background of this disorder. Using modern mass-spectrometric examination methods, micro-array analysis and differential allelic expression, we are looking for the risk genes involved in this disorder.

Furthermore, we cooperate closely with the Max Planck Institute for Human Cognitive and Brain Sciences, e.g. in our project LEGASCREEN, which is described in detail at www.legascreen.de. In this cooperation we are working on methods to combine data from MRI, EEG and genetics.

Offers of the Cognitive Genetics Unit

Differential allelic expression

© Photo Fraunhofer IZI

When examining gene variants, e.g. SNPs, their functional role is of great significance. Whether and to what extent different determined gene variants influence the quantities of the protein produced (expressed) is analyzed via differential allelic expression. We employ a mass-spectrometric method that is capable of providing reliable information on differential allelic expression based on relatively few samples.

DNA isolation / DNA aliquoting

DNA can be obtained from all types of nucleated cells. Its isolation from blood and saliva has proven to be particularly useful. The DNA is purified of contaminants and in this form can either be employed directly or aliquoted in 96- and 384-well microtiter plate format (robot-assisted).

Functional magnetic resonance imaging and imaging genetics

This method is implemented in cooperation with partners at Jena University Hospital, Imperial College London and the Max Planck Institute for Human Cognitive and Brain Sciences. It provides insight into the functionality of the brain while performing different tasks. In this manner it is possible to examine the interaction of different brain regions during complex cognitive performance and with different genetic predispositions.

Diffusion tensor imaging (DTI)

This variant of magnetic resonance imaging is conducted together with the Max Planck Institute for Human Cognitive and Brain Sciences and illustrates the anatomical structure and course of neuronal fiber tracks. Therefore we can study e.g. the degree of myelination and hence the strength of fiber tracks depending on certain genetic variants.

Electroencephalography (EEG)

Using electroencephalography in cooperation with our partners from the Max Planck Institute for Human Cognitive and Brain Sciences and Jena University Hospital, it is possible to study brain activity in high temporal resolution and to detect changes based on certain genetic variants.

Molecular biological analysis of gene variants and statistical evaluation

© Photo Fraunhofer IZI

The DNA portion to be genotyped can be amplified and localized by means of the polymerase chain reaction (PCR) and subsequent single base extension. The actual genotyping is performed in parallel for several variants by so-called multiplexing using a mass spectrometer (MALDI-TOF-MS, Bruker). Corresponding assays can be developed for almost any polymorphisms (SNPs, single base polymorphisms). We employ statistical methods and programs by means of which it is possible to perform genetic-epidemiological evaluations of very large data volumes in an efficient and precise manner.

Reference project: LEGASCREEN – Development of an early test for dyslexia

writing girl
© Photo MEV-Verlag GmbH, Germany

The aim of our project is to develop an early test for dyslexia offering affected children the opportunity of timely therapy. Most of the current methods require reading and writing skills to diagnose dyslexia reliably. Yet those skills are not acquired before school, meaning that existing tests cannot be applied before the end of the second grade.

Our project pursues another way and combines two research approaches: genetics and specific measurements of brain activity (EEG).

Dyslexia is largely genetic and a human’s genetic material (DNA) does not change during the lifespan. Hence appropriate genetic risk variants can be used for a very early diagnosis. Our project will use genetic variants already known to be involved in the development of dyslexia. Furthermore, scientific knowledge concerning the genetics of dyslexia shall be deepened and expanded.

The second central part of our test will be EEG. Research has shown that eventual dyslexics show distinctive features in brain activity already during early childhood.

The conspicuous features of EEG and genetic material shall be combined in our test to develop an early and simple diagnostic independent of reading and writing.

Magnetic resonance imaging (MRI) also used in our study serves as a link between genetics and EEG. Thus we are able to better understand structural features of the brain. These scientific discoveries will help to develop our early test for dyslexia, yet MRI will not be part of the final test.

More information can be found at www.legascreen.de.

The auditory working memory in dyslexia and its genetic basis (DysGen)

The foundations of speech development and their influence on dyslexia shall be studied in cooperation with the Max Planck Institute for Human Cognitive and Brain Sciences. The auditory working memory thereby represents an important component of language processing. Hints exist that it is impaired in a subgroup of dyslexics therefore representing a causal factor for dyslexia. Furthermore, structural differences in grey matter and fiber tracks of persons with good respectively bad auditory working memory are assumed.

The project shall answer the following questions:

  • Are there differences in fiber tracks respectively grey matter of persons with good and bad auditory working memory detectable?
  • Are genes related to dyslexia connected to conspicuousnesses correlations regarding strength / myelination of fiber tracks (e.g. arcuate fasciculus) or  conspicuousnesses in grey matter?

Studies on the auditory thalamus in the course of dyslexia development

In this cooperation project with the Max Planck Institute for Human Cognitive and Brain Sciences differences between dyslexics and controls in the automated post-hypothalamic processing are being studied. We seek to find out if the automated post-hypothalamic processing is changed in dyslexics and to which degree genes are involved.

Genetic basics of dyslexia (PLUTO)

Virtually any disease can be regarded as a result of the combined influences of external environmental factors and internal genetic factors. The relation of these factors involved in disease etiology has been recognized to be surprisingly static. A strong genetic background could even be determined for dyslexia, which was tragically misinterpreted as an intelligence deficit for a long time. As the latter has no influence on intelligence, special teaching and learning techniques can help the affected children, provided they are identified early enough. The earlier these techniques are employed the more effective they are, preferably long before school enrolment. Currently employed assessment tests, however, focus on children of school age – a diagnostic window that is definitely too late.

The project thus aims at developmental steps for a genetic screening test for dyslexia that can be performed at a much earlier stage than the current methods. The genetic markers are identified from candidate genes and a microarray-based screening. The strategy for validating these markers comprises several steps:

  • Genotyping of an independent cohort
  • Characterizing the markers by means of functional magnetic resonance imaging (fMRI)
  • Characterizing the markers with respect to their relevance for the expression quantity of the relevant genes.

The screening test itself comprises neither fMRI nor expression analysis. With this test, the results of a genetic analysis are translated into a clinical assay. Thus, an early identification of children at risk would be possible and the functional regeneration could be facilitated by means of early support.

  • Bruker Daltonics GmbH
  • Imperial College London, Department of Mathematics I
  • Institute for Systemic-Integrative Learning Therapy Leipzig
  • Jena University Hospital, Department of Child and Adolescent Psychiatry and Psychotherapy
  • Max Planck Institute for Human Cognitive and Brain Sciences
  • Max Planck Institute for Psychiatry
  • Research Center Jülich, Institute for Neuro Science and Medicine
  • Sabel Schools
  • Translational Centre for Regenerative Medicine (TRM)
  • University of Bonn, Institute for Human Genetics
  • University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology (IMISE)

Publications

  • Burkhardt J, Blume M, Petit-Teixeira E, Hugo Teixeira V, Steiner A, Quente E, Wolfram G, Scholz M, Pierlot C, Migliorini P, Bombardieri S, Balsa A, Westhovens R, Barrera P, Radstake TR, Alves H, Bardin T, Prum B, Emmrich F, Cornelis F, Ahnert P, Kirsten H. Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression. PLoS One. 2014 Aug 22;9(8):e103872. DOI dx.doi.org/10.1371/journal.pone.0103872.
  • Hass J, Walton E, Kirsten H, Turner J, Wolthusen R, Roessner V, Sponheim SR, Holt D, Gollub R, Calhoun VD, Ehrlich S. Complexin2 modulates working memory-related neural activity in patients with schizophrenia. European Archives of Psychiatry and Clinical Neuroscience. 2014 Oct 9. [Epub ahead of print] DOI dx.doi.org/10.1007/s00406-014-0550-4.
  • Mueller B, Ahnert P, Burkhardt J, Brauer J, Czepezauer I, Quente E, Boltze J, Wilcke A, Kirsten H. Genetic risk variants for dyslexia on chromosome 18 in a German cohort. Genes, Brain and Behavior. 2014 Mar;13(3):350-6. DOI dx.doi.org/10.1111/gbb.12118.
  • Roshyara NR, Kirsten H, Horn K, Ahnert P, Scholz M. Impact of pre-imputation SNP-filtering on genotype imputation results. BMC Genetics. 2014 Aug 12;15:88. DOI dx.doi.org/10.1186/s12863-014-0088-5.
  • Tönjes A, Scholz M, Breitfeld J, Marzi C, Grallert H, Gross A, Ladenvall C, Schleinitz D, Krause K, Kirsten H, Laurila E, Kriebel J, Thorand B, Rathmann W, Groop L, Prokopenko I, Isomaa B, Fasshauer M, Klöting N, Gieger C, Blüher M, Sturmvoll M, Kovacs P. Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin. PLoS Genetics. 2014 Dec 18;10(12):e1004854. DOI dx.doi.org/10.1371/journal.pgen.1004854.
  • Xu LX, Holland H, Kirsten H, Ahnert P, Krupp W, Bauer M, Schober R, Mueller W, Fritzsch D, Meixensberger J, Koschny R. Three gangliogliomas: Results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature. Neuropathology. 2014 Nov 6. DOI dx.doi.org/10.1111/neup.12176.
  • Burkhardt J, Kirsten H, Holland H, Krupp W, Ligges C, Quente E, Boltze J, Ahnert P, Wilcke A. (2012). Association of rs2069459 in the CDK5 gene with dyslexia in a German cohort. Psychiatric Genetics. 22 (2012), 6, S. 307-308. DOI dx.doi.org/10.1097/YPG.0b013e328353aeae.
  • Burkhardt J, Kirsten H, Wolfram G, Quente E, Ahnert P. (2012). Differential allelic expression of IL13 and CSF2 genes associated with asthma. Genetics and molecular biology, 35(2012), 3, S. 567-574. DOI dx.doi.org/10.1590/S1415-47572012005000055.
  • Holland H, Ahnert P, Koschny R, Kirsten H, Bauer M, Schober R, Meixensberger J, Fritzsch D, Krupp W. (2012). Detection of novel genomic aberrations in anaplastic astrocytomas by GTG-banding, SKY, locus-specific FISH, and high density SNP-array. Pathology, research and practice, 208 (2012), 6, S. 325-330. DOI dx.doi.org/10.1016/j.prp.2012.03.010.
  • Kirsten H, Wilcke A, Ligges C, Boltze J, Ahnert P. (2012). Association study of a functional genetic variant in KIAA0319 in German dyslexics. Psychiatric Genetics. 22 (2012), 4, S. 216-217. DOI dx.doi.org/10.1097/YPG.0b013e32834c0c97.
  • Wilcke A, Ligges C, Burkhardt J, Alexander M, Wolf C, Quente E, Ahnert P, Hoffmann P, Becker A, Müller-Myhsok B, Cichon S, Boltze J, Kirsten H. (2012). Imaging genetics of FOXP2 in dyslexia. European Journal of Human Genetics, 20 (2012), 2, S. 224-229. DOI dx.doi.org/10.1038/ejhg.2011.160.
  • Scholz M, Kirsten H. (2011). Comparison of scoring methods for the detection of causal genes with or without rare variants. BMC Proceeding, Suppl. 9, S49.
  • Holland H, Mocker K, Ahnert P, Kirsten H, Hantmann H, Koschny R, Bauer M, Schober R, Scholz M, Meixensberger J, Krupp W. (2011) High- resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas. Cancer Genetics and Cytogenetics, 204(10), 541-9.
  • Holland H, Livrea M, Ahnert P, Koschny R, Kirsten H, Meixensberger J, Bauer M, Schober R, Fritzsch D, Krupp W. (2011) Intracranial hemangiopericytoma: Case study with cytogenetics and genome wide SNP-A analysis. Pathology, Research and Practice, 207(5):310-6.
  • Mocker K, Holland H, Ahnert P, Schober R, Bauer M, Kirsten H, Koschny R, Meixensberger J, Krupp W. (2011). Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics. Pathology, Research and Practice, 207(1), 67-72.
  • Wilcke A, Boltze J. (2010). Genetische Grundlagen der Legasthenie. In: Witruk, E., Teichert, A., Stück, M. (Eds.): Learning, Adjustment, and Stress Disorders. Bern.
  • Wilcke A, Weissfuss J, Kirsten H, Wolfram G, Boltze J, Ahnert P. (2009). The role of gene DCDC2 in German dyslexics. Annals of Dyslexia, 59(1), 1-11.
  • Kirsten H, Burkhardt J, Hantmann H, Hunzelmann N, Vaith P, Ahnert P, Melchers I. (2009). 5HT2A polymorphism His452Tyr in a German Caucasian systemic sclerosis population. Arthritis Research & Therapy, 11(2), 403.
  • Kirsten H, Petit-Teixeira E, Hantmann H, Reichardt J, Burkhardt J, Emmrich F, Cornelis F, Ahnert P. (2009). A family-based study does not support the association of a functional polymorphism in the gene for endothelial nitric oxide synthase with risk for rheumatoid arthritis. Scandinavian Journal of Rheumatology, 38(4), 320-321.
  • Kirsten H, Petit-Teixeira E, Scholz M, Hasenclever D, Hantmann H, Heider D, Wagner U, Sack U, Hugo-Teixeira V, Prum B, Burkhardt J, Pierlot C, Emmrich F, Cornelis F, Ahnert P. (2009). Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study. Arthritis Research & Therapy, 11(3), R60.
  • Jaen O, Petit-Teixeira E, Kirsten H, Ahnert P, Semerano L, Pierlot C, Cornelis F, Boissier MC, Falgarone G, European Consortium on Rheumatoid Arthritis Families. (2009). No evidence of major effects in several Toll-like receptor gene polymorphisms in rheumatoid arthritis. Arthritis Research & Therapy, 11(1), R5.
  • Burkhardt J, Petit-Teixeira E, Teixeira VH, Kirsten H, Garnier S, Ruehle S, Oeser C, Wolfram G, Scholz M, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Bardin T, Prum B, Buchegger-Podbielski U, Emmrich F, Melchers I, Cornelis F, Ahnert P. (2009). Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis. The Journal of Rheumatology, 36(10), 2149-2157.
  • Kirsten H, Blume M, Emmrich F, Hunzelmann N, Mierau R, Rzepka R, Vaith P, Witte T, Melchers I, Ahnert P. (2008). No association between Systemic Sclerosis and the C77G Polymorphism in the Human PTPRC (CD45) Gene. The Journal of Rheumatology, 35(9), 1817-1819.
  • Krupp W, Holland H, Koschny R, Bauer M, Schober R, Kirsten H, Livrea M, Meixensberger J, Ahnert P. (2008). Genome-wide genetic characterization of an atypical meningioma by single-nucleotide polymorphism array-based mapping and classical cytogenetics. Cancer Genetics and Cytogenetics, 184(2), 87-93.
  • Holland H, Koschny R, Krupp W, Meixensberger J, Bauer M, Schober R, Kirsten H, Ganten TM, Ahnert P. (2007). Cytogenetic and molecular biological characterization of an adult medulloblastoma. Cancer Genetics and Cytogenetics,178(2),104-13.
  • Holland H, Koschny R, Krupp W, Meixensberger J, Bauer M, Kirsten H, Ahnert P. (2007) Comprehensive cytogenetic characterization of an esthesioneuroblastoma. Cancer Genetics and Cytogenetics, 173(2), 89-96.
  • Ahnert P, Kirsten H. (2007). Association of ITGAV supports a role of angiogenesis in rheumatoid arthritis. Arthritis Research & Therapy, 9(5), 108.
  • Kirsten H, Teupser D, Weißfuß J, Wolfram G, Emmrich F, Ahnert P. (2007). Robustness of single-base extension against mismatches at the site of primer attachment in a clinical assay. Journal of Molecular Medicine, 85(4), 361-369.
  • Mahr S, Kirsten H, Müller B. (2007). Reply to Loughlin et al. American Journal of Human Genetics, 80(2), 386-7.
  • Kirsten H, Dienst S, Emmrich F, Ahnert P. (2006). CalcDalton: a tool for multiplex genotyping primer design for single-base extension reactions using cleavable primers. Biotechniques, 40(2),158-162.

Patents

  • Wilcke A, Kirsten H, Boltze J, Ahnert P, Gerdes W, Emmrich F. Method of diagnosing dyslexia. European Patent Office No. 08160344.1-2402.
  • Kirsten H, Ahnert P, Boltze J. Method of reducing the molecular weight of at least one PCR product for its detection while maintaining its identity. European Patent Office: Publication Number EP 2180065.
  • Burkhardt J, Kirsten H, Ahnert P, Boltze J. Quantitative determination of cDNA and genomic DNA comprised in a sample. World Intellectual Property Organization: International Publication Number 2010/046454.