1997 — 2000 |
Myers, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Linkage Study in Parkinsons Disease @ Boston University Medical Campus
DESCRIPTION (Adapted from the Investigator's Abstract) The cause of Idiopathic Parkinson's disease (PD), a debilitating disease that afflicts an estimated 1 percent of persons age 60 or older, remains unknown. Research by investigators affiliated with this project and by others have demonstrated a significant familial component in the risk for PD. This proposal is in response to a Program Announcement from the National Institute of Neurological Disorders and Stroke, requesting research into possible genetic factors in the cause of Parkinson's disease. The goal of this project is to begin linkage studies to map genes which predispose to PD risk. To identify regions of the genome containing genes associated with PD risk, the investigators propose a 10 centimorgan density genome scan in 400 affected sibling pairs. Participants will be recruited through a multi-institutional collaboration of ten affiliated clinical sites. The 400 affected sib pairs will consist of two sets of 200 pairs each. The genome scan will be done separately in each set of 200, with the second set providing a mechanism for pursuing promising linkages and replicating significant linkages found in the first set. The investigators will assess possible genetic heterogeneity associated with variation in age at onset, PD family history, and risk factor involvement.
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1 |
2002 — 2006 |
Myers, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Linkage Study in Parkinson's Disease @ Boston University Medical Campus
DESCRIPTION (provided by applicant): The cause of idiopathic Parkinson's disease (PD), a debilitating disease that afflicts an estimated 1 percent of persons age 60 or older, remains unknown. In this application, we propose genetic epidemiological studies, genetic linkage studies, and candidate gene studies for PD. In the past four years, we have established a ulti-institutional research program that has collected 300 PD affected sibling pairs and extended families. Our linkage analyses to onset age revealed evidence for linkage (LOD 2.1) to chromosome 2pl3 at the 'PARK3' locus (Gasser et al. 1998). Recently, we found association (p<0.02) to the same STR marker and allele as seen by Dr. Gasser's group and association to SNP alleles (pC0.008) We also see evidence for linkage to two other loci reported by other groups. Our reported linkage to PD affection on chromosome 9q (DeStefano et al. 2001) is also reported by Scott et al. (2001). Drs. Hardy and Farrer of the Mayo Clinic Jacksonville confirm linkage to chromosome 10q in the same region that we reported for PD affection. Thus, we have detected at least three regions (2p, 9q, and 10q) that harbor PD related genes detected by other groups. These findings confirm that PD is a complex trait, requiring a large well-characterized sample for sufficient power to identify the implicated genes. We propose (AIM 1) genetic epidemiological studies aimed at identifying factors related to penetrance in PD by studying risk factors predicting onset age in sibling pairs who are widely discordant for onset age. This unique sample of sibling pairs permits novel analyses of factors related to penetrance. We propose (AIM 2) to continue our genetic linkage analysis, with a 10cM density genome scan in 350 affected sibling pairs and other family members; 300 of these affected sibling pairs have already been collected. We will assess possible genetic heterogeneity associated with risk factor involvement and PD family history. We have found significant modification of onset age. We propose (AIM 4) to follow-up those regions with evidence for linkage to PD affection or onset age in and additional 350 PD sib pairs to be collected in this study. We further propose association studies to localize candidate genes. Finally, we propose (AIM 5) a focused candidate gene study for PD, concentrating primarily on genes and genomic regions implicated in dystonia, due to overlapping clinical features of PD and dystonia. This project has great potential to expand our knowledge of the genetics of PD and to identify PD associated genes and risk factors and patterns for their interaction.
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1 |
2002 — 2007 |
Myers, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epidemiological and Genetic Studies of Body Mass Index @ Boston University Medical Campus
DESCRIPTION (provided by applicant): Increased levels of Body Mass Index (BMI) are associated with increased mortality and morbidity from cardiovascular disease, hypertension, diabetes and other disorders. The recent dramatic increase in obesity in the American population has reached epidemic proportions, with two-thirds of the general population meeting criteria for "over-weight" and one-third meeting criteria for "obese". While the increase in the prevalence of obesity reflects changing lifestyle and dietary habits, genetic factors are shown to influence the susceptibility for obesity. Animal and human studies reveal that a high-calorie/high fat-diet produces substantial differences in weight gain on different genetic backgrounds. Understanding the genes that influence susceptibility to obesity will permit investigation into treatment to prevent or reduce weight gain and reverse the population trend for increasing obesity. The NHLBI Family Heart Study (FHS) found compelling linkage for BMI (LOD = 4.9) on chromosome 7q31-q34. This region has been implicated in at least sixteen other genome scans for obesity and related traits, and may be the most widely replicated locus in obesity genetics. We believe the FHS sample to be the largest study of the region and to provide the best opportunity to identify the implicated genes. This group of investigators has worked extensively with the FHS, the Framingham Study, and the Family Blood Pressure Program Project, and has performed genome scans in these large study samples. The 4.9 LOD for BMI to chromosome 7q31-q34 is the largest reported for any trait in these studies. Yet genome scans have little value if they are not followed by gene discovery. We suggest that this application offers a unique opportunity to fulfill the purpose of those scans. Over the past 2 years and 2 months we have genotyped 421 SNPs in the 7q31-q34 region, and SNP linkage in our focus sample generates a LOD = 16 for BMI. We will show compelling evidence for a haplotype in the 5' region of the Leptin gene (p<0.00005) influencing BMI among men in our sample. We will further demonstrate that the responsible gene in this region is not Leptin. SNP and haplotype association studies implicate three strong candidate loci and other loci also warrant additional study. We propose to confirm SNP association in an independent study of 200 families showing linkage to the same position (from Dr. R. Arlen Price's group). Those loci with confirmed association will be further characterized by sequencing, genotyping new polymorphisms, and gene expression studies to identify the responsible genes. The proposed studies offer a unique opportunity to discover important BMI related genes at 7q31.
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1 |
2011 — 2015 |
Myers, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Markers in Huntington's Disease Brain @ Boston University Medical Campus
DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded CAG tract in the HD gene that results in gradual loss of memory, cognitive skills and normal movements. Multiple lines of research point to dysregulated transcription as a prevailing feature of HD pathology and suggest that altered histone modification by the mutant protein (Htt) may contribute to this process. However, thus far there has been no genome-wide analysis of histone modifications in human HD brain. The studies proposed here apply novel genomic technology to the search for epigenetic signatures in HD brains with the goal of gaining insight into HD pathogenesis. Our proposal capitalizes on two unique resources: (1) a novel FACS-ChIP-seq method which we will apply to establish and compare the methylomes of neurons from HD and control brains; and (2) a unique sample of HD brains, including a set matched for CAG repeat expansion (range 42-44 repeats) but onset ages differing by 30 years or more. The brains have been extensively neuropathologically characterized for degree of both striatal and cortical involvement. Since we found that histone H3 methylation markings in HD brains overlap highly with the signal in CD4+ cells, we are also comparing the altered epigenetic signature seen in HD brain to that in blood samples at varying stages of disease (presymptomatic, early and advanced HD) as this may offer a novel epigenetic biomarker in HD blood. Such biomarkers are of translational significance for the evaluation of drug treatments to realign the disrupted gene expression. We have preliminary data using the FACS-ChIP-Seq method in six HD prefrontal cortex samples and eleven normal controls, which provides tantalizing evidence for the significance of the proposed studies and demonstrates our capabilities to apply the techniques and to meaningfully interpret the findings. Our approach represents the most comprehensive analysis to date addressing the role of histone methylation in HD pathogenesis. Regardless of outcome, these studies will provide critical new insights into the molecular pathways of HD pathogenesis and may also uncover novel molecular targets for HD treatment. The high translational impact of this proposal is increased by our proposal to identify and characterize a unique histone methylation biomarker in HD blood cells. If successful, identification of such a biomarker will greatly facilitate clinical trials for novel HD therapies and offers a novel method to evaluate whether new drug treatments rectify disrupted gene expression.
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2011 — 2013 |
Myers, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Characterization of the Role of Cyclin G-Associated Kinase in Parkinson Disease @ Boston University Medical Campus
DESCRIPTION (provided by applicant): Our genome wide association study (GWAS) for familial Parkinson's disease (PD) was the first to identify the cyclin G-associated kinase (GAK) gene as associated with PD risk. Meta-PD GWAS analyses have now demonstrated an unequivocal genome-wide effect (at least P = 4.8 x 10-15) for the rs1564282 SNP in the GAK gene on increased PD risk. Notably, the effect appears to be particularly strong in familial PD. Recently, we published that GAK is associated with 1-synuclein toxicity. Microarray expression analysis of post-mortem frontal cortex from PD and control brains found a significant association of rs1564282 with increased 1- synuclein expression, which has implications for disease pathogenesis. Further, knockdown of GAK significantly increases 1-synuclein toxicity in neuronal cell models of PD. GAK plays a critical role in endocytosis through its interaction with cathepsin-D (CTSD), which is the main lysosomal enzyme involved in 1-synuclein degradation. Taken together, these studies implicate a novel role for GAK in PD pathogenesis. Since kinases, such as GAK, are attractive targets for therapeutic intervention, resolving the responsible functional variants in the GAK gene region and their effects on GAK's expression and function promise important advancements for PD research and therapeutics. This application proposes to identify the responsible mutations, and to further evaluate their role in the implicated endocytic pathway and in the pathogenesis of PD. We propose a definitive series of DNA sequencing, RNA sequencing, alternative splicing, gene expression, and clinical risk profiling studies which have important translational implications. Specifically, Aim 1 will identify functional sequence variants in the GAK region by resequencing 225 Kb in 480 familial PD cases and 96 controls from our GenePD familial PD cohort, in which the gene was identified, thus greatly enhancing the likelihood for successful discovery of functional variants. Aim 2 proposes to perform RNA-sequencing in a large well characterized series of 34 PD and 29 control brains, for which extensive SNP genotyping and microarray data are already available. The RNA-Seq data will be used to study coding sequence and expression of GAK and related genes in the endocytic pathway. RNA sequencing will also allow us to examine all the GWAS implicated PD genes (e.g. SNCA, MAPT, BST1 etc.) and to perform transcriptome-wide comparison of cases and controls. Finally, Aim 3 explores the characteristics of PD cases carrying the variants and mutations found in Aims 1 and 2 and utilizes the genotyping of identified sequence variants in gene-gene and gene- environment interaction and genetic risk profiling studies. Genetic risk profiling studies have important translational implications in risk prediction and diagnostics for PD as well as for interpretation of therapeutic response in clinical trials for PD. These PD investigators are uniquely experienced with the GAK gene and region and have already in hand all the samples needed to carry out these definitive studies.
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1 |
2014 — 2018 |
Jaenisch, Rudolf [⬀] Myers, Richard H Young, Richard |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
An Ipsc Based Platform For Functionally Assessing Genetic and Environmental Risk @ Whitehead Institute For Biomedical Res
DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common chronic progressive neurodegenerative disease worldwide, with a prevalence of more than 1% in the population over the age of 60, thus constituting a major global health problem of the aging population. The disease is primarily characterized by a major loss of nigrostriatal dopaminergic neurons but the genetic etiology leading to the neuronal cell loss has largely remained unknown. Numerous genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that point to more than 50 genomic loci containing risk variants for sporadic PD. However the identified risk variants predominantly map to poorly understood non-coding regions of the genome, which has impeded functional and molecular understanding of how these genetic variants contribute to the increased risk for PD. Importantly, it has been established that PD GWAS associated loci are typically non-coding and mediate allele-specific effects on distal gene expression, consistent with a central role for disruption on enhancer element function in PD pathogenesis Human induced pluripotent stem cell (hiPSC) technology offers for the first time the unique opportunity to study sporadic diseases whose genetic components are poorly understood, by allowing for the generation of human patient-derived somatic cells such as midbrain dopaminergic neurons which carry all the genetic alterations that contributed to the development of the disease. The overall goal of this project is to establish a transformational paradigm, which overcomes the substantial technical limitations of the iPS system and creates a genetically defined experimental in vitro system for studying the molecular and biological mechanisms of sporadic PD in the dish. To achieve this, we will establish a novel experimental framework to link descriptive GWAS PD hits to genomic regulatory enhancer elements and establish functional assays for connecting PD risk alleles to the expression of disease relevant effector genes. Our aim is to gain molecular understanding of the complex interactions between multiple genetic risk alleles and to identify key genes of which the expression level affects the PD specific cellular phenotype. To identify functional relevant candidate risk variants (PD-eQLTs) we will link PD associated risk alleles to genomic regulatory (enhancer) elements that are relevant for gene activity in neurons by establishing an enhancer map in cultured homogenous dopaminergic neurons as well as in sorted neuronal nuclei from human brain. Insights into these interactions will facilitate devising rational therapeutic strategies. This experimental in vitro platform will be used to define the interactions of environmental risk factors with the genetic determinants that have been predicted from GWA studies to predispose to PD (GxE).
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0.91 |