Anthony P Monaco

• MD, PhD
• University Professor and President emeritus at Tufts University

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, m...

Prevalence rates of mental health disorders in children and adolescents have increased two to threefold from the 1990s to 2016. Some increase in prevalence may stem from changing environmental conditions in the current generation which interact with genes and inherited genetic variants. Current measured genetic variant effects do not explain fully...

Repeated testing of a population is critical for limiting the spread of the SARS-CoV-2 virus and for the safe reopening of educational institutions such as kindergarten—grade 12 (K-12) schools and colleges. Many screening efforts utilize the CDC RT-PCR based assay which targets two regions of the novel Coronavirus nucleocapsid gene. The standard ap...

Throughout evolution, there has been interaction and exchange between RNA pools in the environment, and DNA and RNA pools of eukaryotic organisms. Metagenomic and metatranscriptomic sequencing of invertebrate hosts and their microbiota has revealed a rich evolutionary history of RNA virus shuttling between species. Horizontal transfer adapted the R...

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis...

Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. While previous studies have identified common genetic variants associated with dyslexia, the role of rare variants has only recently begun to emerge from pedigree studies and has yet to be systematically te...

Clinical characteristics: VPS13A disease, caused by VPS13A loss-of-function pathogenic variants, is characterized by a spectrum of movement disorders (chorea, dystonia, tics, sometimes parkinsonism); predominant orofacial choreic and dystonic movements and tics (with involuntary tongue protrusion on attempted swallowing, habitual tongue and lip bi...

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were...

Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0...

The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be in...

Reading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet no convincing genetic markers have been found due to limited study power. Here, we present a genome-wide association study representing...

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 227...

Repeated testing of a population is critical for limiting the spread of the SARS-CoV-2 virus and for the safe reopening of educational institutions such as K-12 schools and colleges. Many screening efforts utilize the CDC RT-PCR based assay which targets two regions of the novel Coronavirus nucleocapsid gene. The standard approach of testing each p...

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, rapi...

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early post‐mortem studies conducted in the 1980s linked the disorder to subtle defects in t...

Study of knockout (KO) mice has helped understand the link between many genes/proteins and human diseases. Identification of infertile KO mice provides valuable tools to characterize the molecular mechanisms underlying gamete formation. The KIAA0319L gene has been described to have a putative association with dyslexia; surprisingly, we observed tha...

Developmental dyslexia (DD) is one of the most prevalent learning disorders among children and is characterized by deficits in different cognitive skills, including reading, spelling, short term memory and others. To help unravel the genetic basis of these skills, we conducted a Genome Wide Association Study (GWAS), including nine cohorts of readin...

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early post-mortem studies conducted in the 1980s linked the disorder to subtle defects in t...

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early post-mortem studies conducted in the 1980s linked the disorder to subtle defects in t...

Developmental dyslexia is a neurodevelopmental disorder that affects reading ability caused by genetic and non-genetic factors. Amongst the susceptibility genes identified to date, KIAA0319 is a prime candidate. RNA-interference experiments in rats suggested its involvement in cortical migration but we could not confirm these findings in Kiaa0319-m...

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in ne...

KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 particip...

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously-implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels...

Background: Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association sp...

Galectin-12, a member of the galectin family of β-galactoside-binding animal lectins, is preferentially expressed in adipocytes and required for adipocyte differentiation in vitro. This protein was recently found to regulate lipolysis, whole body adiposity, and glucose homeostasis in vivo. Here we identify VPS13C, a member of the VPS13 family of va...

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P< 0.5x10−8) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biolog...

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate line...

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), bu...

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a Genome-wide Association Scan (GWAS) meta-analysis using three richly characterised datasets comprising individuals with histories of reading or la...

Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, onl...

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping kno...

CD38 encodes a ligand in the oxytocin signaling pathway. Some single nucleotide polymorphisms in this gene have been associated with low serum oxytocin levels in autism spectrum disorder (ASD) patients. Oxytocin disruption has been hypothesized to account for features of ASD, including impaired communication and social behavior, based on animal stu...

Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects...

Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association anal...

Mitochondrial Ca2+ uptake has key roles in cell life and death. Physiological Ca2+ signaling regulates aerobic metabolism, whereas pathological Ca2+ overload triggers cell death. Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter complex in the inner mitochondrial membrane1, 2, which comprises MCU, a Ca2+-selective ion channel, and its reg...

Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, inclu...

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728...

The transporter ATP7A mediates systemic copper absorption and provides cuproenzymes in the trans-Golgi network (TGN) with copper. To regulate metal homeostasis, ATP7A constitutively cycles between the TGN and plasma membrane (PM). ATP7A trafficking to the PM is elevated in response to increased copper load and is reversed when copper concentrations...

Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals...

The Menkes disease ATPase (MNK) is a copper transporter that localizes to the mammalian trans-Golgi network (TGN) and shows substantial co-localization wih a ubiquitous TGN resident protein and marker, TGN46. We tested our hypothesis that these two TGN residents and integral membrane proteins are localized to biochemically distinct TGN sub-compartm...

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of...

The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD...

There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene...

SHANK2E expression in human multiple tissue panel and in rat embryos. A. Quantitative RT-PCR in human tissues. Primers and probe were designed to detect SHANK2E isoform. GAPDH was used for the ΔCt calculation and total brain was used as the reference for relative quantification calculation (RQ ± SEM). B. In situ hybridization of rat fetus sagittal...

Characterization and validation of the SHANK2 CNV in family AU038. A. Pedigree of the AU038 family showing that the deletion is de novo on the maternal chromosome. SNPs were genotyped using the Illumina 1M duo array. B. SHANK2 CNV validation by quantitative PCR of exon E4–E6, E15–E17 of SHANK2 using genomic DNA from the father, mother and the proba...

Clinical description of the patients carrying predicted deleterious SHANK2 variations. Abbreviations: ADI-R, Autism Diagnosis Interview-Revised; ASD, autism spectrum disorder; CT, computed tomography; ERG, electroretinogram; F, female; FSIQ, full scale IQ; HC, head circumference; K-ABC, Kaufman Assessment Battery for Children; M, male; MRI, magneti...

Frequency of SHANK2 R818H variation in 948 individuals from the Human Genome Diversity Panel. (DOC)

Evolutionary conservation of SHANK2 protein sequence. Variations identified only in patients with ASD, only in controls or shared by patients and controls are indicated in red, green and orange, respectively. Hu, human; Ch, chimpanzee; Ma, macaque; Ra, rat; Mo, mouse; Ck, chicken; Zn, zebrafinsh; Zf, zebrafish; Xe, xenopus. (DOC)

Primers used for mRNA analysis of SHANK2 isoforms. * Primers were used for relative quantification study of SHANK2E isoform. The other primers were used for RT-PCR analysis of each SHANK2 isoform. (DOC)

Primers used for mutation screening. (DOC)

Description of the population of patients with ASD analyzed in this study. (DOC)

Distribution of SHANK2 variants affecting conserved or non conserved amino acids. All variants came from this study (26) and from Berkel et al. 2010 (24). *Several variants shared by patients with ASD and controls were identified in both studies. (DOC)

Primers used for in vitro mutagenesis. (DOC)

Primers used for CNV validation. (DOC)

Pedigree of families with ASD carrier of non-synonymous SHANK2 mutations. Variations specific to ASD or shared by ASD and controls are indicated in red and orange, respectively. Clinical phenotypes are specified in the figure. (TIF)

Functional analysis of shank2 mutations in cultured hippocampal neurons. A. Rat hippocampal neurons transfected with wild-type or mutated ProSAP1A/SHANK2-EGFP cDNA constructs were detected by EGFP expression. B. The quantification of dendrite number was performed on 20 transfected hippocampal neurons per construct from at least 3 independent experi...

Frequency of SHANK2 R818H variation in 3250 patients with ASD and 2013 controls. OR, odds ratio; P, p-value. (DOC)

List of all CNVs observed in ASD patients carrying a de novo deletion of SHANK2. The 6319_3 and 5237_3 patients were described by the AGP [9]. QSNP, QuantiSNP; PCNV, PennCNV; IP, iPattern. (DOC)

Clinical comparison of patients with ASD carrying SHANK2 variants with the rest of the cohort of patients. We used the Wilcoxon test for the continuous traits and the Fisher's exact test (2-sided) for the discontinuous traits. OR is given with 95% confidence interval. OR, odds ratio; P, p-value; ADI-R, Autism Diagnosis Interview revised. (DOC)

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery...

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritabil...