First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children

• Published in: Molecular psychiatry Vol. 16; no. 1; pp. 97 - 107
• Main Authors: ROESKE, D, LUDWIG, K. U, MÜLLER-MYHSOK, B, NÖTHEN, M. M, SCHULTE-KÖRNE, G, NEUHOFF, N, BECKER, J, BARTLING, J, BRUDER, J, BROCKSCHMIDT, F. F, WARNKE, A, REMSCHMIDT, H, HOFFMANN, P
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.01.2011
• Subjects: Adolescent; At risk youth; Biological and medical sciences; Case-Control Studies; Child; Child & adolescent psychiatry; Children & youth; Chromosomes, Human, Pair 4; Contingent Negative Variation - genetics; Discrimination (Psychology) - physiology; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Dyslexia; Dyslexia - genetics; Evoked Potentials, Auditory - genetics; Female; Genetic aspects; Genome-Wide Association Study; Genomes; Genomics; Glucose; Glucose Transporter Type 3 - genetics; Humans; Male; Medical sciences; Memory; Nervous system (semeiology, syndromes); Neurology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychotherapy; Reference Values; Speech; Speech Perception - genetics; Teenagers; Topography; Young Adult; Germany; Reading disorder; Central nervous system; Stimulus disparity; Electrophysiology; Cognition; Verbal perception; Glucose; Language disorder; Encephalon; Endophenotype; Electrodiagnosis; Mismatch negativity; Acoustic stimulus; Language; glucose transporter; Dyslexia; Child; Carrier protein; Human; expression; speech perception; Neurophysiology; Communication disorder; Auditory evoked potential; Speech
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2009.102

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.