Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

Characteristics of sleep EEG power spectra in healthy infants in the first two years of life.

OBJECTIVE: This study characterises and describes the maturational evolution of the healthy infant sleep electroencephalogram (EEG) longitudinally from 2 weeks to 24 months of age, by means of power spectral analysis. METHODS: A prospective cohort of 34 healthy infants underwent overnight polysomnography (PSG) at 2 weeks, and at 3, 6, 12 and 24 months of age. Sleep epochs were scored as Active Sleep (AS) and Quiet Sleep (QS) at 2 weeks of age and as Rapid Eye Movement (REM) and Non-REM (NREM) stages from 3 months onwards. Representative epochs were used to generate the EEG power spectra, from the central C3 derivation. These were analysed visually and quantitatively in AS/REM and QS/NREM sleep in the following bandwidths: delta (0.5-4 Hz); theta (4-8 Hz); alpha (8-11 Hz); sigma (11-15 Hz) and 0.5-25 Hz. RESULTS: Sleep EEG (central derivation) power spectra changed significantly in the different bandwidths as the infants matured. The emergence of a peak in the sigma bandwidth in NREM N2 sleep corresponded with the development of sleep spindles. Maturational changes were also seen in NREM N3 and in theta and alpha bandwidths in both AS/REM and QS/NREM. CONCLUSIONS: Sleep EEG power spectra characteristics in healthy infants evolve in keeping with maturation and neurodevelopmental milestones. SIGNIFICANCE: This study provides an atlas of healthy infant sleep EEG in the early years of life, providing a basis for association with other neurodevelopmental measures and a normative dataset on which disease may be discriminated.

WITHDRAWN: NaS1 sulfate transporter is linked to hyposulfatemia and longevity.

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Analysis of N- and O-linked protein glycosylation in children with Prader-Willi syndrome.

BACKGROUND: Current genotype-phenotype correlations in Prader-Willi syndrome (PWS) are struggling to give an explanation of the diversity in phenotype and there is a need to move towards a molecular understanding of PWS. A range of functions related to glycoproteins are involved in the pathophysiology of PWS and it may be that abnormal glycosylation is contributing to the biological phenotype. The objective of this study was to investigate the state of N- and O-linked glycosylation in children with Prader-Willi syndrome. METHODS: Twenty-three children with PWS and 20 non-PWS controls were included in the study. Protein N-linked glycosylation was assessed by analysing serum transferrin through mass spectrometry and protein O-linked through isoelectric focusing (IEF) of serum apolipoprotein C-III (apoC-III), confirmed by mass spectrometry. RESULTS: The results of this analysis indicated that the N-linked glycosylation pathway in PWS is normal. A subgroup of PWS individuals was found to have a hyposialylated pattern of apoC-III isoforms. This was independent of the underlying genetic mechanism and is the first report of an apoC-III IEF abnormality in PWS. CONCLUSIONS: This is the first report of apoC-III hyposialylation in PWS. As this field is in its infancy, additional study is required before these findings may be used in clinical settings.

Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly.

Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE.