Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ～10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.     

Das Na-Transportsystem während der Erregungsprozesse am Ranvier-Knoten isolierter markhaltiger Nervenfasern

Summary (1) An attempt is made to interpret the action potential of medullated nerve fibres of the frog in terms of permeability changes to Na ions.(2) In keeping with a suggestion byHodgkin andHuxley, the following assumptions are made: (a) a carrier system is responsible for transporting Na ions across the nodal membrane; (b) in a resting fibre (high membrane potential) its transport capacity is small; (c) depolarization has a dual effect on the transport system, namely activation of carrier groups as a quick reaction and inactivation of the whole system as a slower reaction.(3) The following experimental observations are interpreted on the ground of these assumptions: threshold for depolarization, threshold for repolarization, absolute and relative refractory period, alteration of the action potential on application of a hypertonic (5%) NaCl solution.

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Eine vorläufige Mitteilung erfolgte auf der Tagung des Schweiz. Vereins für Physiologie usw. in Fribourg 1956. Helv. physiol. Acta14, C35–36 (1956).