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• PRDM9 loss of function follow up from Born-in-Bradford Autozygosity sequencing

  In the autozygosity exome sequencing of Born-in-Bradford samples of Pakistani origin there is a mother who is homozygous for an apparent truncating stop codon in PRDM9, the gene responsible for localising recombination during meiosis. We plan to deep sequence mother and child with X10, and physically phase the mother with PacBio sequencing. We will use this data to identify recombination locations, and test whether these are consistent with the known fine scale recombination map. Data Access is controlled by the Wellcome Trust Sanger Institute DAC and the Born In Bradford Executive Group.

  Dataset EGAD00001001686

• Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)

  CHD is the leading cause of death in the United States. One of the most common ways to prevent CHD is to take an anti-platelet agent, which lessens platelet aggregation. Two of the most common anti-platelet agents are aspirin and clopidogrel. However, up to 25% to 30% of people do not respond to these medications. Evidence indicates that treatment response may be related to genetics. The purpose of this study is to determine specific gene variants that predict response to aspirin and clopidogrel therapy. This study is part of a larger group of studies called the Pharmacogenomics Research Network (PGRN). Participants are from the Old Order Amish of Lancaster, Pennsylvania. They are well suited for genetic studies because they are a homogenous, closed, founder population. Participants received 300 mg of clopidogrel on the first day, then 75 mg of clopidogrel per day for the next 6 days. On the last day of clopidogrel treatment, participants took a single dose of 324 mg aspirin. Participants underwent platelet function tests before and after clopidogrel alone, and then again after taking clopidogrel plus aspirin. Using the gene variation profiles across the genome, researchers analyzed which variants correspond to treatment response.

  Study phs000391

• Identification and Targeting of Inflammatory Macrophage-Fibroblast Crosstalk in Rheumatoid Arthritis

  Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, redirecting them into a state is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions. Reprinted from Kuo, Ding et al., Science Translational Medicine 2019, PMID: 31068444, with permission from American Association for the Advancement of Science.

  Study phs001340

• Genetic analysis of Hirschsprung disease

  Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5,000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and Congenital Central Hypoventilation syndrome (CCHS). Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described. The goal of the research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families using whole genome mapping and sequencing studies with functional follow-up of candidate genes and variants. We intend to ascertain the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Clinical information is collected to allow investigation of possible genotype - phenotype correlations. The subject population consists of individuals diagnosed with HSCR and their unaffected relatives. Individuals/families are ascertained through support groups, web-based listings of research studies and genetic testing services, an educational study website, and referrals from genetic counselors and physicians. Blood, or tissue, samples are requested from affected individuals and their unaffected relatives.

  Study phs000497

• Creatine in Huntington's Disease (HD) (CREST-E)

  This is a multi-center, randomized, double-blind, placebo-controlled trial of creatine monohydrate involving 553 ambulatory subjects with HD who are not requiring skilled care or institutionalization. Eligible subjects were randomized to receive up to 40 grams daily of creatine monohydrate or matching placebo. Randomization will be followed by a Titration Phase, a Maintenance Phase, an Optional Extended Maintenance Phase, and Washout. During the Titration Phase, which may last up to six months, study drug will be initially escalated in 5-gram increments starting at 5 g/day until the 40 g/day target dose is reached. Should subjects be unable to reach or stay at the maximum dose during the Titration Phase, they will remain on the highest tolerated dose (HTD) for which they have no significant side effects. During the Maintenance Phase, subjects will be followed prospectively and systematically. Subjects completing 36 months of follow-up on study drug will be eligible to continue in the study for an additional twelve months of follow-up in the Extended Maintenance Phase. The primary measure of efficacy is the annualized rate of change in TFC. The primary hypothesis of the study is that chronic treatment of early-stage HD subjects with creatine monohydrate will slow the progressive functional decline of HD.

  Study phs001488

• Sporadic Amyotrophic Lateral Sclerosis (ALS): Parent-Offspring and Twin Sequencing Study

  Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that affects the nerves in the brain and spinal cord, leading to muscle weakening and eventual paralysis and death. Ten percent of ALS cases are thought to be familial while the majority of cases are sporadic and the causative factors unknown. Dr. Roger Pamphlett of the University of Sydney has collected a unique cohort of consented trios where the child has ALS but the parents are unaffected. Since the age of onset is so late, it is very difficult to obtain this kind of trio. We have performed whole exome sequencing on these trios to identify de novo and recessive germline variants associated with sporadic ALS. In addition, Dr. Pamphlett has assembled a collection of consented discordant monozygotic twins, where one twin has ALS and the other is unaffected. We performed whole genome sequencing on these twin pairs to identify postzygotic variants that may contribute to sporadic ALS susceptibility. Finally, we have the opportunity to compare the sequence and gene expression in affected and unaffected tissues from blood, brain and/or spinal cord samples from consented ALS patients to look for somatic mutations or gene expression changes that may further our understanding of the disease.

  Study phs000831

• Integrated Personal omics Processing (iPoP) Longitudinal multi-omics profiling of prediabetes

  Type 2 diabetes mellitus (T2D) is a significant health problem. Close to 20 million individuals in the United States have T2D, and 79 million aged 20 years or older are clinically pre-diabetic, with a 5-year conversion rate of 10% to 23% from prediabetes to T2D. In a collaborative effort to systematically understand diabetes and its etiology, the team is comprised of leading experts in research on both the human host as well as the microbiome, as properties of both are likely relevant in T2D development. For a better elucidation of mechanisms of onset and progression of T2D disease, the group is performing a detailed analysis of the biological processes that occur in the microbiome and human host by longitudinal profiling of patients at risk for T2D. Both microbiome and host profiles are being analyzed by state-of-the-art omics platforms, and these large-scale and diverse data sets will be integrated to determine the dynamic pathways that change during the onset and progression of T2D, especially during viral infections and other stresses. This longitudinal study is expected to reveal changes in the microbiome and host at an unprecedented level of detail, and identify molecules and pathways that play important roles in diabetes onset and progression.

  Study phs001719

• Longitudinal Study of Bone and Endocrine Disease in Children with MPS I, II, and VI: A Multicenter Study of the Lysosomal Disease Network

  Mucopolysaccharidoses (MPS) I, II, and VI are a group of rare, lysosomal storage diseases in which certain enzymes are missing that are normally required for breaking down specific complex carbohydrates. Deficiencies in these enzymes result in the build-up of toxic substances in various tissues and cause damage to the body's organs. In the past, children diagnosed with MPS I, II, or VI frequently died in early to late childhood. Recent advances in treatments including hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT) have been helping children with these disorders live into adulthood. The long term-course of the disease is now unknown. Unfortunately, severe skeletal disease persists for most individuals despite current therapies. This is a longitudinal study of 50 children and adults with MPS I, II, and VI. Study participants will be evaluated every year for up to 3 years. The purpose of this study is to document the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets. This information is needed to: determine long-term benefits and limitations of current treatments including HCT or ERT direct development of further treatment options improve clinical care for children affected by the disorder

  Study phs001576

• Somatic Mutation Profile by Next Generation Sequencing in HER2+ Breast Cancer

  The HER pathway is the driving force behind 30% of human breast cancers. It is important to understand how targeted therapies block different cellular pathways, and mechanisms of escape from this blockage. Therapies directed at HER2 establish a successful treatment paradigm, but de novo and acquired resistance exist. The HER signaling system is a complex network with four receptors and eleven ligands, a phosphorylation signaling cascade, and many transcription factors, all complicated by both positive and negative feedback circuits. Analysis of genomes, exomes and transcriptomes by next generation sequencing is aimed at uncovering the genetic factors responsible for patient responses to HER2-directed therapies. We are sequencing HER2-overexpressing cancers, in order to identify potential somatic changes that may better select patients who will benefit from therapy, to determine new targets that may overcome resistance, and to improve outcomes with known current HER2-targeted therapies. Whole exome capture sequencing will determine somatic mutation profiles in HER2-overexpressing tumors, to comprehensively characterize the somatic alterations, with the goal of identifying those patients most likely to respond, as well as discovering new targets that may overcome resistance to HER2-directed therapy. We augment the whole exome data with RNA-seq data to determine expression levels of somatic mutations we discover.

  Study phs000770

• Rapid Evolution of a Skin Lightening Allele in Southern African KhoeSan

  The genetic architecture and polygenicity of skin pigmentation is explored in KhoeSan communities, including Nama individuals whose phenotype and genotype data are provided in this dataset. By pairing genotypes and quantitative spectrophotometric skin pigmentation phenotypes, we show that skin pigmentation is highly heritable in KhoeSan, yet known pigmentation loci only explains a small fraction of the phenotypic variance. Using genome-wide association analyses, we identified both canonical and non-canonical skin pigmentation loci. We show that this phenotype is more polygenic and complex than previously characterized. (Martin et al., Cell 2017. PMID: 29195075) Following up on the top associated signal with large effect size in the gene SLC24A5, we demonstrate that the canonical Eurasian nonsynonymous allele was introduced into KhoeSan via a recent migration ~2 kya and was under extremely strong selection. The derived allele was present at high frequency despite controlling for gene flow. With high-throughput sequences in the captured SLC24A5 region, we show that the most common derived haplotype is identical amongst Europeans, eastern African and KhoeSan. Using 4-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 ya via a back-to-Africa migration and then experienced a selective sweep.

  Study phs001753