First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children.
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.
Roeske
D
D
Max-Planck Institute of Psychiatry, Munich, Germany.
Ludwig
K U
KU
Neuhoff
N
N
Becker
J
J
Bartling
J
J
Bruder
J
J
Brockschmidt
F F
FF
Warnke
A
A
Remschmidt
H
H
Hoffmann
P
P
Müller-Myhsok
B
B
Nöthen
M M
MM
Schulte-Körne
G
G
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002894:Chromosomes, Human, Pair 4; D003265:Contingent Negative Variation / Q000235:genetics; D004192:Discrimination, Psychological / Q000502:physiology; D004410:Dyslexia / Q000235:genetics*; D005072:Evoked Potentials, Auditory / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D051274:Glucose Transporter Type 3 / Q000235:genetics*; D006801:Humans; D008297:Male; D012016:Reference Values; D013067:Speech Perception / Q000235:genetics*; D055815:Young Adult
D051274:Glucose Transporter Type 3; C495687:SLC2A3 protein, human