Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder

<p><b>Objectives:</b> Elucidating the biological mechanisms involved in attention-deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age.</p> <p><b>Methods:</b> We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted.</p> <p><b>Results:</b> From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected <i>P</i> = 0.016; OR = 2.27 95%CI: 1.15–4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected <i>P</i> = 0.007; OR = 3.30 95%CI: 1.33–8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin.</p> <p><b>Conclusions:</b> Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD.</p

Gestational age within normal range and infants’ health and temperament at 3-months of age

<p><b>Objective:</b> To examine the association between gestational age (GA) at birth across the normal GA spectrum (37–41 weeks) and the temperament and health of 3-month old infants.</p> <p><b>Methods:</b> The sample comprised 242 “low-risk” mothers and infants without chronic illnesses or severe pregnancy complications. Infant temperament was defined by three constructs: Negative Affectivity (NA), Extraversion, and Regulation, assessed by parents’ reports on the Infant Behavior Questionnaire. Infants’ health was defined as the number of nonroutine doctors’ visits attended by the infants since their release from the hospital after birth. Analyses employed a continuous measure of GA to assess outcomes across GAs and a categorical measure (37, 38, 39–41 weeks GA) to examine contrasts.</p> <p><b>Results:</b> Extraversion was positively related to GA primarily due to the <i>lower</i> scores of infants born at 37 weeks compared to infants born at 39–41 weeks GA. NA showed a similar effect. The odds of infants born at 37 weeks attending a nonroutine medical visit were 2.8 times that of infants born full-term.</p> <p><b>Discussion:</b> Infants born at 37 weeks GA express less affect and use more nonroutine medical services than do infants born at 39–41 weeks GA. The findings underscore the importance of considering the risks of pregnancy prolongation with the developmental risk associated with early-term delivery.</p

Genetic analysis for cognitive flexibility in the trail-making test in attention deficit hyperactivity disorder patients from single nucleotide polymorphism, gene to pathway level

<p><b>Objectives</b>: Investigation of the genetic basis of endophenotype and analysis the pathways with multiple genes of small effects might increase the understanding of the genetic basis of attention deficit hyperactivity disorder (ADHD). Here we aimed to explore the genetic basis of cognitive flexibility in ADHD at the single nucleotide polymorphism (SNP), gene and pathway levels.</p> <p><b>Methods:</b> The trail-making test was used to test the cognitive flexibility of 788 ADHD patients. A genome-wide association analysis of cognitive flexibility was conducted for 644,166 SNPs.</p> <p><b>Results</b>: The top SNP rs2049161 (<i>P</i> = 5.08e-7) involved gene <i>DLGAP1</i> and the top gene <i>CADPS2</i> in the gene-based analysis resulted in much literature evidence of associations with psychiatric disorders. Gene expression and network analysis showed their contribution to cognition function. The interval-enrichment analysis highlighted a potential contribution of ‘adenylate cyclase activity’ and <i>ADCY2</i> to cognitive flexibility. Candidate pathway-based analysis for all SNPs found that glutamate system-, neurite outgrowth- and noradrenergic system-related pathways were significantly associated with cognitive flexibility (FDR <0.05), among which the neurite outgrowth pathway was also associated with ADHD symptoms.</p> <p><b>Conclusions</b>: This study provides evidence for the genes and pathways associated with cognitive flexibility and facilitate the uncovering of the genetic basis of ADHD.</p

Genome-wide nonparametric LOD scores of two indices attaining genome-wide significance in the nested OSA linkage analyses over 22 autosomal chromosomes.

<p>Genome-wide nonparametric LOD scores of two indices attaining genome-wide significance in the nested OSA linkage analyses over 22 autosomal chromosomes.</p

Flow chart of the estimation of chromosome-wide significance (left panel) and genome-wide significance (right panel) for a maximum subset-based logarithm of odds (LOD) in the ordered subset analysis (OSA) and nested OSA of genetic linkage in 557 families of siblings co-affected with schizophrenia.

<p>Flow chart of the estimation of chromosome-wide significance (left panel) and genome-wide significance (right panel) for a maximum subset-based logarithm of odds (LOD) in the ordered subset analysis (OSA) and nested OSA of genetic linkage in 557 families of siblings co-affected with schizophrenia.</p

Flow chart of the ordered subset analysis (OSA) and nested OSA of genetic linkage in 557 families of siblings co-affected with schizophrenia.

<p>CPT, Continuous Performance Test; WCST, Wisconsin Card Sorting Test; LOD, logarithm of odds.</p

Distribution of age at onset, CPT scores, and WCST scores in affected siblings.

a<p>The adjusted z scores were derived by means of standardizing the raw scores with adjustments for sex, age, and education against our norm data.</p>b<p>Cut-off at the lowest 25% of data.</p>c<p>Cut-off at the lowest 75% of data.</p><p>*<i>P</i><0.0001 for the t-test examining if the adjusted z scores significantly different than 0.</p

Nested ordered-subset analysis in the subgroup with early-onset schizophrenia by CPT or WCST.

a<p>Families were randomly permuted for 1000 times with respect to the covariate ranking and a chromosome-wide p value for each chromosome was yielded.</p>b<p>Significance level derived from simulations; a genome-wide empirical p-value <0.0015 [i.e., 0.05/33 covariates)] is denoted in boldface as reaching genome-wide significance.</p><p>*<i>P</i><0.0001 for the mixed effect model comparing the families covariate values between the nested subset of families and the remaining ones.</p

Participant characteristics.

<p>Participant characteristics.</p

Three-way interactions of <i>DAT1</i> and <i>5-HTT</i> with positive peer affiliation and age² on total brain volume.

<p>(A & B) Three-way interaction between <i>DAT1</i>, positive peer affiliation, and age² on total gray matter volume, shown separately for low (A; - 2SD) and high positive peer affiliation (B; + 2SD). (C & D) Three-way interaction between <i>5-HTT</i>, positive peer affiliation, and age² on total gray matter volume, shown separately for low (C; - 2SD) and high positive peer affiliation (D; + 2SD). Regression lines show predicted values. <i>P</i>-values indicate significant slopes and significant slope differences.</p