Familiality of neural preparation and response control in childhood attention deficit-hyperactivity disorder

Background Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n=97), their non-affected siblings (n=27) and control children without a family history of ADHD (n=43). Results Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. Conclusions Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorde

Visual word form processing deficits driven by severity of reading impairments in children with developmental dyslexia

The visual word form area (VWFA) in the left ventral occipito-temporal (vOT) cortex is key to fluent reading in children and adults. Diminished VWFA activation during print processing tasks is a common finding in subjects with severe reading problems. Here, we report fMRI data from a multicentre study with 140 children in primary school (7.9-12.2 years;55 children with dyslexia, 73 typical readers, 12 intermediate readers). All performed a semantic task on visually presented words and a matched control task on symbol strings. With this large group of children, including the entire spectrum from severely impaired to highly fluent readers, we aimed to clarify the association of reading fluency and left vOT activation during visual word processing. The results of this study confirm reduced word-sensitive activation within the left vOT in children with dyslexia. Interestingly, the association of reading skills and left vOT activation was especially strong and spatially extended in children with dyslexia. Thus, deficits in basic visual word form processing increase with the severity of reading disability but seem only weakly associated with fluency within the typical reading range suggesting a linear dependence of reading scores with VFWA activation only in the poorest readers

Cross Section Measurements of High-p(T) Dilepton Final-State Processes Using a Global Fitting Method

The authors present a new method for studying high-p{sub T} dilepton events (e{sup {+-}}e{sup {-+}}, {mu}{sup {+-}}{mu}{sup {-+}}, e{sup {+-}}{mu}{sup {-+}}) and simultaneously extracting the production cross sections of p{bar p} {yields} t{bar t}, p{bar p} {yields} W{sup +}W{sup -}, and p{bar p} {yields} Z{sup 0} {yields} {tau}{sup +}{tau}{sup -} at a center-of-mass energy of {radical}s = 1.96 TeV. They perform a likelihood fit to the dilepton data in a parameter space defined by the missing transverse energy and the number of jets in the event. The results, which use 360 pb{sup -1} of data recorded with the CDF II detector at the Fermilab Tevatron Collider, are {sigma}(t{bar t}) = 8.5{sub -2.2}{sup +2.7} pb, {sigma}(W{sup +}W{sup -}) = 16.3{sub -4.4}{sup +5.2} pb, and {sigma}(Z{sup 0} {yields} {tau}{sup +}{tau}{sup -}) = 291{sub -46}{sup +50} pb

Precision measurement of the top quark mass from dilepton events at CDF II

We report a measurement of the top quark mass, M{sub t}, in the dilepton decay channel of t{bar t} {yields} b{ell}{prime}{sup +} {nu}{sub {ell}}, {bar b}{ell}{sup -}{bar {nu}}{sub {ell}} using an integrated luminosity of 1.0 fb{sup -1} of p{bar p} collisions collected with the CDF II detector. We apply a method that convolutes a leading-order matrix element with detector resolution functions to form event-by-event likelihoods; we have enhanced the leading-order description to describe the effects of initial-state radiation. The joint likelihood is the product of the likelihoods from 78 candidate events in this sample, which yields a measurement of M{sub t} = 164.5 {+-} 3.9(stat.) {+-} 3.9(syst.) GeV/c{sup 2}, the most precise measurement of M{sub t} in the dilepton channel

Analysis of the quantum numbers J**PC of the X(3872)

The authors present an analysis of angular distributions and correlations of the X(3872) in the exclusive decay mode X(3872) {yields} J/{psi}{pi}{sup +}{pi}{sup -} with J/{psi} {yields} {mu}{sup +}{mu}{sup -}. They use 780 pb{sup -1} of data from p{bar p} collisions at {radical}s = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. They derive constraints on spin, parity, and charge conjugation parity of the X(3872) by comparing measured angular distributions of the decay products with predictions for different J{sup PC} hypotheses. The assignments J{sup PC} = 1{sup ++} and 2{sup -+} are the only ones consistent with the data

Chromatin Organization in Sperm May Be the Major Functional Consequence of Base Composition Variation in the Human Genome

Chromatin in sperm is different from that in other cells, with most of the genome packaged by protamines not nucleosomes. Nucleosomes are, however, retained at some genomic sites, where they have the potential to transmit paternal epigenetic information. It is not understood how this retention is specified. Here we show that base composition is the major determinant of nucleosome retention in human sperm, predicting retention very well in both genic and non-genic regions of the genome. The retention of nucleosomes at GC-rich sequences with high intrinsic nucleosome affinity accounts for the previously reported retention at transcription start sites and at genes that regulate development. It also means that nucleosomes are retained at the start sites of most housekeeping genes. We also report a striking link between the retention of nucleosomes in sperm and the establishment of DNA methylation-free regions in the early embryo. Taken together, this suggests that paternal nucleosome transmission may facilitate robust gene regulation in the early embryo. We propose that chromatin organization in the male germline, rather than in somatic cells, is the major functional consequence of fine-scale base composition variation in the human genome. The selective pressure driving base composition evolution in mammals could, therefore, be the need to transmit paternal epigenetic information to the zygote

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p <1 x 10(-8)) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 10(-8)), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [10(-8)-10(-17)]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.Peer reviewe

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 x 10(-8)) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene;rs17663182 p = 4.73 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter;rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 10(-8)), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [10(-8)-10(-17)]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits