3613 results for "*geneti*"

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• Frontotemporal Dementia and Related Disorders: Transcriptomic Profiling, Biomarker Discovery, and Mechanistic Insight

  Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) lie on a disease spectrum, characterized by overlap in diagnosis, pathology, and underlying genetics. The most prominent of the overlapping genetic causes is a repeat expansion in the gene C9orf72, which is the most common cause of both FTD and ALS. Our study aims to identify the transcriptomic signature of C9orf72-related FTD and ALS by studying post-mortem human brain tissue. Specifically, here we integrated long-read and short-read RNA sequencing data to comprehesively characterize the human frontal cortex, evaluating FTD and ALS patients with the C9orf72 repeat expansion, FTD and ALS patients without the C9orf72 repeat expansion, and controls. Our analysis consisted of transcript classification and annotation, differential gene and transcript analysis, and splicing burden analysis. In total, we found over 1,000 differentially expressed transcripts, including nearly 200 of which that were classified as novel compared to a human reference. Notably, some of these differentially expressed transcripts contained cryptic exons present in genes known to be regulated by TDP-43, like STMN2, while others have not been previously shown (e.g., DRC1). As use to the research community, we have created a shiny application web browser (link: __) that allows for exploration of all transcripts that we detected.

  Study phs004442

• Genetic Studies of Glomerular Diseases

  This ongoing study investigates the genetic basis of idiopathic nephrotic syndrome (INS) and related glomerular diseases, including focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). We hope to identify genetic factors associated with disease susceptibility and clinical heterogeneity.Eligible participants include individuals of any age, sex, gender, race, or ethnicity with a clinical diagnosis of primary nephrotic syndrome. Individuals with known secondary causes of nephrotic syndrome, including diabetes- or obesity-associated glomerular disease, or kidney biopsy findings consistent with alternative primary or secondary glomerular diseases (e.g., membranous nephropathy or autoimmune kidney disease), were excluded. Written informed consent was obtained from all participants or legal representatives.Participants were recruited primarily through the Division of Nephrology at Columbia University Irving Medical Center and the Division of Pediatric Nephrology at Morgan Stanley Children's Hospital, with additional enrollment through collaborating centers in Europe and South America.

  Study phs004810

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659

• Investigations of Genetic Variation in Families Affected by MUTYH-Associated Polyposis

  Defects in the Base-Excision Repair gene, MUTYH, are known to increase colorectal cancer risk through a recessive Mendelian pattern and raise mutation rates in both normal somatic and germline mammalian cells. In this study, we employed whole genome sequencing (WGS) of fifteen human individuals (representing 4 related families) at 50X coverage to examine germline de novo mutation rates in a large family with pathogenic MUTYH mutations and a history of colorectal cancer. We used an in vitro cell line assay to determine the family's genotype (p. Y179C/V234M, transcript NM_001128425) partially attenuates MUTYH's function. The children of mothers affected by the biallelic pathogenic genotype were associated with a moderate increase in the C>A mutation rate, but this effect was determined to be lower than previously reported mutator effects for other biallelic pathogenic MUTYH genotypes. No similar mutation rate increase was found in children of fathers with the same genotype despite calculating that we should have adequate power to detect such a mutator effect, indicating that MUTYH's role in repairing oxidative stress might be more significant in female reproductive aging than in males. We used a combination of in vitro cell line assays and bioinformatics pipelines to assess the impact of the MUTYH genotype on germline mutation rates. The study design ensures that sufficient statistical power was available to detect mutator effects in both maternal and paternal lineages. The sequencing data generated from this study include single sample genotype files derived from WGS, focusing on germline DNA. The phenotypic data at individual level and sequence data can be accessed by authorized users, facilitating further exploration of the relationship between MUTYH pathogenic variants and colorectal cancer risk.

  Study phs003554

• Interrogating Gene Regulation During Human Cortical Development

  Our study investigates the regulatory function and evolutionary origins of the fastest evolved genomic regions in the human genome termed Human Ancestor Quickly Evolved Regions (HAQERs), during human cortical development. Single-cell RNA sequencing (scRNA-seq) data were generated from human cortical progenitor cells from 4 individuals spanning the second trimester of development, subjected to pooled CRISPR interference (CRISPRi) perturbations targeting 50 HAQERs using an all-in-one lentiviral vector. Bulk ATAC-seq was performed using the same 4 human subjects to prioritize the 50 accessible HAQERs to be silenced. Single cell RNA sequencing libraries were generated using the 10x Genomics chromium high-throughput 3′ gene expression platform under lentiviral transduction with high MOI, low MOI, and low MOI under Wnt pathway stimulation. To enable assignment of individual donors in multiplexed single-cell experiments, genotypes were obtained using the Illumina Global Screening Array.

  Study phs004522

• Normal Pressure Hydrocephalus

  Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. 

  Study phs002296

• Contextual and Health Behavior Effects on Epigenetic Aging Among Africans in the Family and Community Health Studies

  The Family and Community Health Studies (FACHS) is a longitudinal examination of health and health related behaviors in African American families. The original study cohort consisted of 867 African American parent-child dyads from Georgia and Iowa who were ascertained in cooperation with local school districts. The key inclusion criteria for participating in the study were the presence of an adolescent in the 5th grade (approximately 10-11 years old) who self-identified as African American (i.e., the Target) and the participation of a primary caretaker (PC) for the Target. The clinical and biological data included in this collection are from the Target (i.e., FACHS-T) portion of these studies of these African American parent-child dyads. The initial wave of behavioral assessments of the FACHS-T subjects was conducted in 1997-98 (Wave 1), with seven subsequent ascertainments, Wave 2 (1999–2000), Wave 3 (2002–2003), Wave 4 (2005–2006), Wave 5 (2007–2009), Wave 6 (2010–2011), Wave 7 (2014–2016) and Wave 8 (2019-2021). Full interviews were obtained at each wave of the study with the exact content of the wave varying as a function of developmental age. These interviews of the FACHS-T subjects collected a wide variety of data including the following: perceived discrimination; socioeconomic status; substance use exposure; common internalizing and externalizing disorders such as depression, substance use, and conduct disorder; school efficacy; peer support and perceived parenting practices. Biological sampling of the FACHS-T subjects was conducted at three time points. Saliva DNA was collected at Wave 5 while full phlebotomy was conducted at Waves 7 and 8. The genome wide methylation data listed below is derived from the whole blood DNA samples collected at Wave 8 and Wave 9. The genome wide genotyping data was determined using DNA from the Wave 7 samples. The clinical and biological data available herein are those from 309 FACHS-T subjects who participated in both Wave 7 and Wave 8, and who consented for deposition of their data in dbGAP.

  Study phs003723

• Genetic Investigations of Attention-Deficit/Hyperactivity Disorder

  Design and Aims:We conducted whole-exome DNA sequencing on 152 parent-child trios (456 individuals total) that included a child meeting DSM-IV or DSM-5 criteria for ADHD along with both biological parents to identify rare de novo damaging DNA variants associated with ADHD risk. Mutation rates were compared between 147 ADHD trios and 780 unaffected control trios. We aimed to identify specific ADHD risk genes by combining the de novo trio data with rare variant data from an independent case-control cohort.Population Information:ADHD trios were collected from four sites. The 780 control trios were unaffected siblings from the Simons Simplex Collection who scored in the normal range on the Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) ADHD subscale.Molecular Technologies:Whole-exome DNA sequencing was performed on the ADHD trios using the IDT xGen V1 or Agilent SureSelect All Exon V7 capture and the Illumina NovaSeq6000 sequencer. Control trios were previously sequenced with the NimbleGen SeqCap EzExomeV2 capture and Illumina HiSeq 2000 sequencer. Joint variant calling was performed for all trios. Rare de novo variants with allele frequency Principal Findings:We found a 1.67-fold enrichment of rare de novo damaging variants and a 1.93-fold enrichment of ultra-rare de novo damaging variants in ADHD cases vs controls. By integrating the de novo data with an independent case-control cohort, KDM5B was identified as a high-confidence ADHD risk gene (FDR=0.04). Three potential risk genes were also identified. Twenty-three genes with ultra-rare damaging de novo variants in ADHD overlapped with previously reported risk genes for other neuropsychiatric conditions. Exploratory analyses showed enrichment of these genes in early neurodevelopmental pathways.

  Study phs003647

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Multiethnic Cohort

  The genetic basis of cardiovascular disease in individuals of non-European ancestry remains largely unknown. Availability of ethnically diverse study populations is essential to investigate the underlying causes of disease.The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex, inherited diseases. The Multiethnic Cohort (MEC) of the University of Hawaii Cancer Center and the University of Southern California comprises primarily five ethnic groups: Caucasians, Japanese Americans, Native Hawaiians, African Americans and Latinos. This study contains whole genome sequence data derived from participants in the MEC cohort identified as having early onset coronary artery disease.

  Study phs003499

• Acute Respiratory Distress Syndrome Clinical Network: Fluid and Catheter Treatment Trial (ARDSNet FACTT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-FACTT include plasma, DNA, and serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: This study evaluated the benefits and risks of Pulmonary Artery Catheters (PACs) in patients with established acute lung injury in a trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol.Background: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary organ perfusion.Participants: This randomized study compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology. Design: Participants were randomly assigned to a strategy involving either conservative or liberal use of fluids with concealed allocation in permuted blocks of eight with the use of an automated system. Participants were simultaneously and randomly assigned to receive either a pulmonary-artery catheter or a central venous catheter in a two-by-two factorial design.Conclusions: There was no significant difference in the primary outcome of 60-day mortality; however, the conservative strategy of fluid management was associated with improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non-pulmonary organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (NEJM June 15, 2006; Vol 354, No. 24, pp 2564-75; NEJM May 25, 2006; Vol 354, No. 21, pp 2213-24)

  Study phs004165