The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713522 CpG sites from 9537 participants

Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease and type 2 diabetes) and cardiometabolic risk factors in two-sample

Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown.

AbstractThe metabolic needs for postnatal growth of the human nervous system are vast. Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause postnatal undergrowth of brain, and cognitive and motor disability. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival. These metabolic

The use of external controls in genome-wide association study (GWAS) can significantly increase the size and diversity of the control sample, enabling high-resolution ancestry matching and enhancing the power to detect association signals. However, the aggregation of controls from multiple sources is challenging due to batch effects, difficulty in identifying genotyping errors, and the use of different

AbstractAge-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. Genetic variants in the complement factor H (CFH) gene are associated with AMD, but the functional consequences of many of these variants are currently unknown. In this study we aimed to determine the effect of 64 rare and low frequency variants in the CFH gene on systemic levels of

AbstractSeveral pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy

AbstractRecently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism

Limb-girdle muscular dystrophy 3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex (DAPC) crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded

AbstractThe purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer’s disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies

AbstractGenome-wide association studies (GWAS) have identified ~ 20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett’s esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle

Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetically heterogeneous neurologic disorder clinically characterized by focal seizures with auditory symptoms and/or aphasia. About 20% of ADLTE families segregate disease-causing heterozygous mutations in RELN, a brain-expressed gene encoding the secreted protein Reelin. Using a cell-based secretion assay, we show that pathogenic RELN mutations

Germline activating mutations in HRAS cause Costello Syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via ROS-dependent AMPKα and p38 hyperactivation, occurs in CS, resulting

The retinal pigment epithelium of the vertebrate eyes acquires vitamin A from circulating retinol binding protein for chromophore biosynthesis. The chromophore covalently links with an opsin protein in the adjacent photoreceptors of the retina to form the bipartite visual pigment complexes. We here analyzed visual pigment biosynthesis in mice deficient for the retinol binding protein receptor STRA6

GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional

Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5%-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence, impaired adaptive behavior, and often visual impairments. Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) is an interacting partner of the FMR protein, whose loss results in fragile

Recent advances in next generation sequencing, deep networks and other bioinformatic tools have enabled us to mine huge amount of genomic information about living organisms in the post-microarray era. However, these tools do not explicitly factor in the role of the underlying DNA biochemistry (particularly, DNA hybridization) essential to life processes. Here, we focus more precisely on the role that

Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like

Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants

Expanded CAG/CTG repeat disorders affect over 1 in 2500 individuals worldwide. Potential therapeutic avenues include gene silencing and modulation of repeat instability. However, there are major mechanistic gaps in our understanding of these processes, which prevent the rational design of an efficient treatment. To address this, we developed a novel system, ParB/ANCHOR-mediated Inducible Targeting

The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear

The UN General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference (COP26) in Glasgow, UK. Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled

Haploinsufficiency of RAI1 is responsible for Smith-Magenis Syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity, and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1

Nonobstructive azoospermia (NOA) is an important cause of male infertility, and the genetic pathogenesis is still incompletely understood. The previous study reported that heterozygous mutation of c.346-1G > A in SOHLH1 was identified in two NOA patients and suggested it is the pathogenic factor for NOA. However, in our research, this heterozygous mutation was confirmed in three Chinese infertile patients

Myotonic dystrophy type 1 (DM1) is a complex disease with a wide spectrum of symptoms. The exact relationship between mutant CTG repeat expansion size and clinical outcome remains unclear. DM1 congenital patients (CDM) inherit the largest expanded alleles, which are associated with abnormal and increased DNA methylation flanking the CTG repeat. However, DNA methylation at the DMPK locus remains understudied

The purpose of our study is to understand the protective effects of small molecule ligands for phosphorylated tau (p-tau) in Alzheimer’s disease (ad) progression. Many reports show evidence that p-tau is reported to be an important contributor to the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in ad neurons. In ad, glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent

We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57–67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10−7), with a 0.7 to 3.0 standard deviation increase (3 CpGs)

Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological

Nephronophthisis (NPH) is the most prevalent monogenetic disorder leading to end-stage renal failure (ESRD) in childhood. Mutations in Nphp1, encoding a cilia-localized protein, account for the majority of NPH cases. Despite its identification many years ago, Nphp1 deletions targeting exon 4 or exon 20 have not reproduced the histological features of human NPH in murine models. In this study, we deleted

Sperm fibrous sheath is closely related to sperm maturation, capacitation and motility, and A-kinase anchor protein 4 (AKAP4) is the most abundant protein in sperm fibrous sheath. Previous studies found incomplete sperm fibrous sheaths and abnormal flagella in Akap4 knockout (KO) mice. Meanwhile, it was reported that the partial deletion in AKAP4 is highly relevant to the dysplasia of the fibrous sheath

Although more than 80 psoriasis genetic risk loci have been reported through genome-wide association studies (GWASs), the genetic mechanism of psoriasis remains unclear.

Leukemia inhibitory factor (LIF) can influence development by increasing cell proliferation and inhibiting differentiation. Because of its potency for expanding stem cell populations, delivery of exogenous LIF to diseased tissue could have therapeutic value. However, systemic elevations of LIF can have negative, off-target effects. We tested whether inflammatory cells expressing a LIF transgene under

Charcot–Marie-Tooth (CMT) is a commonly inherited, non-fatal neurodegenerative disorder that affects sensory and motor neurons in patients. More than 90 genes are known to cause axonal and demyelinating forms of CMT. The p.R158H mutation in the pyruvate dehydrogenase kinase 3 (PDK3) gene is the genetic cause for an X linked form of axonal CMT (CMTX6). In vitro studies using patient fibroblasts and

AbstractThe gene content of the X and Y chromosomes has dramatically diverged during evolution. The ensuing dosage imbalance within the genome of males and females has led to unique chromosome-wide regulatory mechanisms with significant and sex-specific impacts on X-linked gene expression. X inactivation or silencing of most genes on one X chromosome chosen at random in females profoundly affects the

Alzheimer’s disease (ad) adversely affects the health, quality of life and independence of patients. There is a critical need to identify novel blood gene biomarkers for ad risk assessment. We performed a transcriptome-wide association study to identify biomarker candidates for ad risk. We leveraged two sets of gene expression prediction models of blood developed using different reference panels and

AbstractFriedreich ataxia (FRDA) is a serious hereditary neurodegenerative disease, mostly accompanied with hypertrophic cardiomyopathy, caused by the reduced expression of frataxin (FXN). However, there is still no effective treatment. Our previous studies have shown that SS-31, a mitochondrion-targeted peptide, is capable to upregulate the expression of FXN and improve the mitochondrial function

TAR DNA binding protein 43 (TDP-43) is an RNA processing protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear TDP-43 mislocalises in patients to the cytoplasm, where it forms ubiquitin-positive inclusions in affected neurons and glia. Physiologically, cytoplasmic TDP-43 is associated with stress granules (SGs). Here, we explored TDP-43

AbstractAmyloid-β (Aβ) accumulation in the brain triggers the pathogenic cascade for Alzheimer’s disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aβ production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we

PROPPINs are phosphoinositide-binding β-propeller proteins that mediate membrane recruitment of other proteins and are involved in different membrane remodeling processes. The main role of PROPPINs is their function in autophagy, where they act at different steps in phagophore formation. The human PROPPIN WIPI4 (WDR45) forms a complex with ATG2 involved in phagophore elongation, and mutations in this

Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, predisposition to cancer and developmental defects including hypogonadism. Reproductive defects leading to germ cell aplasia are the most consistent phenotypes seen in FA mouse models. We examined the role of the nuclear FA core complex gene Fancg in the development of primordial germ cells (PGCs), the embryonic

AbstractGenotype imputation is widely used in genetic studies to boost the power of GWAS, to combine multiple studies for meta-analysis and to perform fine mapping. With advances of imputation tools and large reference panels, genotype imputation has become mature and accurate. However, the uncertain nature of imputed genotypes can cause bias in the downstream analysis. Many studies have compared the

Spinal muscular atrophy (SMA) is caused by the loss of the survival motor neuron 1 (SMN1) gene function. The related SMN2 gene partially compensates but produces insufficient levels of SMN protein due to alternative splicing of exon 7. Evrysdi™ (risdiplam), recently approved for the treatment of SMA, and related compounds promote exon 7 inclusion to generate full-length SMN2 mRNA and increase SMN protein

Ogt-mediated O-GlcNAcylation is enriched in the nervous system, and involves in neuronal development, brain function and neurological diseases. However, the roles of Ogt and O-GlcNAcylation in embryonic neurogenesis has remained largely unknown. Here, we show that Ogt is highly expressed in embryonic brain, and Ogt depletion reduces the proliferation of embryonic neural stem cells and migration of

An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children

The application of genomics to medicine has accelerated the discovery of mutations underlying disease and enhanced our knowledge of the molecular underpinnings of diverse pathologies. As the amount of human genetic material queried via sequencing has grown exponentially in recent years, so too has the number of rare variants observed. Despite progress, our ability to distinguish which rare variants

Hereditary colorectal cancer syndromes attributable to high penetrance mutations represent 9–26% of young-onset colorectal cancer cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly

The Y chromosome is the most gene-deficient chromosome in the human genome (though not the smallest chromosome), and has largely been sequestered away from large-scale studies of the effects of genetics on human health. Here I review the literature, focusing on the last two years, for recent evidence of the role of the Y chromosome in protecting from or contributing to disease. While many studies have

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASD) for which microarrays, whole exome sequencing (WES) and whole genome sequencing (WGS) have yielded over a hundred causal loci. Genome-wide association studies (GWAS) in

Alternative splicing has emerged as a fundamental mechanism for the spatiotemporal control of development. A better understanding of how this mechanism is regulated has the potential not only to elucidate fundamental biological principles, but also to decipher pathological mechanisms implicated in diseases where normal splicing networks are mis-regulated. Here, we took advantage of human pluripotent

Genome-wide association studies indicate that SCN10A plays an important role in cardiac electrophysiology. Common and rare SCN10A variants are suggested to contribute to Brugada Syndrome (BrS), an inherited channelopathy resulting from genetic-determined loss-of-function in cardiac sodium channel. This study sought to characterize the role of SCN10A common variants in BrS.

Genome-wide association studies (GWAS) have successfully identified loci of the human genome implicated in numerous complex traits. However, the limitations of this study design make it difficult to identify specific causal variants or biological mechanisms of association. We propose a novel method, AnnoRE, which uses GWAS summary statistics, local correlation structure among genotypes, and functional

The recent accomplishment of a truly complete human genome has afforded a new view of chromosome structure and function that was limited 30 years ago. Here, we discuss the expansion of knowledge from the early cytological studies of the genome to the current high resolution genomic, epigenetic, and functional maps that have been achieved by recent technology and computational advances. These studies

A deficiency in Survival Motor Neuron (SMN) protein results in motor neuron loss in spinal muscular atrophy (SMA) patients. Human SMN is encoded by SMN1 and SMN2 that differ by a single C6T transition in a splice regulatory region of exon 7. In SMN2, exon 7 is skipped leading to an unstable protein, which cannot compensate for SMN1 loss in SMA patients. The disease severity of human SMA (Types 1 to

Patients with autosomal dominant SPECC1L variants show syndromic malformations, including hypertelorism, cleft palate and omphalocele. These SPECC1L variants largely cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1lΔEx4) lacking the entire SPECC1L protein. Homozygous mutants

Chagas disease is an infection caused by the parasite Trypanosoma cruzi, endemic in Latino America. Leveraging the three-way admixture between Native American (AMR), European (EUR) and African (AFR) populations in Latin Americans, we aimed to better understand the genetic basis of Chagas disease by performing an admixture mapping study in a Colombian population. A two-stage study was conducted, and

We have previously established Induced Pluripotent Stem cell (iPSC) models of Huntington's Disease (HD), demonstrating CAG-repeat-expansion-dependent cell biological changes and toxicity. However, the current differentiation protocols are cumbersome and time consuming, making preparation of large quantities of cells for biochemical or screening assays difficult. Here, we report the generation of Immortalized

The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from

Over the past thirty years (the timespan of a generation), advances in genomics technologies have revealed tremendous and unexpected variation in the human genome and have provided increasingly accurate answers to long-standing questions of how much genetic variation exists in human populations and to what degree the DNA complement changes between parents and offspring. Tracking the characteristics