The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits.

Introduction: Co-occurrence of substance use disorders (SUD) and other behavioral conditions, such as stress-related, aggressive or risk-taking behaviors, in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) have been previously identified as key neurotransmitters for some of these phenotypes, we explored the genetic contribution of these pathways to SUD and these comorbid phenotypes in order to better understand the genetic relationship between them.

Methods: We tested the association of 275 dopaminergic genes and 176 serotonergic genes with these phenotypes by performing gene-based, gene-set and transcriptome-wide association studies in 11 genome-wide association studies (GWAS) datasets on SUD and related behaviors.

Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivity and/or Inattention.

Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities.

Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders.

Psychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette's syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls.

Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses.

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures.

Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes.

Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes.

Background: Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism.

Methods: We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100).

A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence.

Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover.

Lack of replication of previous autism spectrum disorder GWAS hits in European populations.

Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059).

Common and rare variants of microRNA genes in autism spectrum disorders.

Objectives: MicroRNAs (miRNAs) are post-transcriptional regulators that have been shown to be involved in disease susceptibility. Here we explore the possible contribution of common and rare variants in miRNA genes in autism spectrum disorders (ASD).

Methods: A total of 350 tag SNPs from 163 miRNA genes were genotyped in 636 ASD cases and 673 controls.

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.

Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations.

Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.

Impairment of language abilities is a common feature in autistic individuals. Heterozygous mutations in the Forkhead Box P2 (FOXP2) gene lead to a severe spoken language disorder. Recently, several studies have pinpointed the involvement of common variants of the Contactin-Associated Protein-Like 2 (CNTNAP2) gene, whose transcription is regulated by the product of FOXP2, in several disorders characterized by language impairments such as autism, specific language impairment (SLI), and selective mutism (SM).

Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects.

Background: Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency.

Objective: To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated.