GTAC

Principal Investigator: Summer Gibson
Keywords: ALS , Amyotrophic Lateral Sclerosis , motor neuron disease , neuromuscular , Lou Gehrig's disease Department: Neurology
IRB Number: 00090406 Co Investigator: Summer Gibson
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, ALS,
Recruitment Status: Not yet recruiting

Contact Information

Teresa Janecki
teresaj@genetics.utah.edu
801-581-3724

Brief Summary

Aim 1: Identify and prospectively phenotype 1500 ALS/MND patients with paired DNA, RNA and iPSC-ready PBMC samples. In addition to creating a rich clinical dataset to be paired with whole-genome and RNA-seq data, this aim will create a library of PBMCs with detailed clinical and genomic characterization for future conversion into iPSC resources.

Aim 2: Generate, annotate, and analyze whole-genome and RNA sequencing for 1500 ALS/MND patients. Important analyses from whole-genome sequencing will include i) identifying rare variants in predicted regulatory sequences for exploration in Aim 3, ii) finding participants with mutations in known disease genes, and iii) investigating potentially oligogenic influences on disease. Analysis of the RNA-seq dataset for expression and splicing patterns that distinguish ALS/MND patients from controls or correlate with specific disease characteristics, thereby  identifying potential biomarkers for diagnosis or sub-groups of similar patients.

Aim 3: Integrate whole-genome sequence data with RNA-seq derived transcriptome data and clinical phenotypes for 1500 ALS/MND patients. Analyses of this integrated dataset will allow the common and rare candidate regulatory mutations identified in Aim 2 to be validated as eQTLs via detectable changes in corresponding gene(s) expression or novel splicing and to be correlated to aspects of disease phenotype.

Detailed Description

The promise of “precision medicine” is already being translated into clinically actionable information in oncology, where the genetic profile of a specific tumor strongly influences a cancer's behavior or prognosis, and in some cases directs which therapies will be most beneficial. Because ALS/MND risk and disease behavior are both highly genetic, additional efforts are needed to uncover the genomic variation that will sub-classify patients, forecast their disease course, and predict responses to emerging therapies. The last decade has witnessed remarkable progress in the genetics of ALS/MND, with a growing proportion of both familial and sporadic cases now genetically “explained”. Despite this progress, the vast majority of ALS/MND cases remain genetically unexplained. Two key steps are broadly recognized as critical to the next phase of ALS/MND genetics. First, genetic studies need to shift from archived samples with minimal or modest clinical data available to focus on prospectively followed ALS/MND patients with current clinical contact. This approach will allow rapid correlation of causal mutations with detailed clinical phenotypes, and will lay the foundation for genetically stratified trials. Second, genetic studies need to move beyond a focus on protein-coding regions (e.g. exome sequencing) to interrogate the full genome through whole genome sequencing. This project takes both of these steps and aims to enable a paradigm shift in the way ALS/MND patients are treated by linking clinical, treatment and outcome information to the genetic lesion(s) underlying the patient’s ALS/MND pathogenesis. To achieve this goal, the GTAC study will enroll and actively follow 1500 ALS/MND patients, prospectively collect harmonized clinical data, enable patient re-contact, generate whole genome sequence data, and develop an appropriate framework for identifying regulatory mutations in patients with ALS/MND through the paired analyses of their genome sequence and high resolution RNA-seq data from accessible peripheral leukocytes. The framework will focus not only on mapping cis- and trans-acting eQTLs, but will also deploy new prioritization schemes that integrate knowledge of ENCODE defined regulatory regions, interactome data, conservation, and population genetic variation data. While an explicit aim of the work is to identify regulatory variants influencing ALS/MND risk, there will also be a focus on developing the appropriate framework for identifying disease-related regulatory mutations. This proof-of-concept study will outline a framework for generating large cohorts of ALS/MND patients with detailed clinical phenotyping, whole-genome sequence, and RNA sequence data. The resulting dataset will be broadly accessible, providing an invaluable resource to the ALS/MND community. In addition to its potential for important discoveries, this project will create two invaluable resources for ALS/MND research. First, the dataset will be made openly and freely available to other researchers. Second, we will generate a repository of PBMCs from participants with complete clinical and genomic data that will be immediately ready for conversion into pluripotent stem cell lines to enable modelling a broad-range of clinical and genetic subtypes of ALS/MND. Finally, we intend to create a detailed framework for even broader-scale integration of genomic, transcriptomic, and clinical data in ALS/MND. Aim 1: Identify and prospectively phenotype 1500 ALS/MND patients with paired DNA, RNA and iPSC-ready PBMC samples. In addition to creating a rich clinical dataset to be paired with whole-genome and RNA-seq data, this aim will create a library of PBMCs with detailed clinical and genomic characterization for future conversion into iPSC resources. Aim 2: Generate, annotate, and analyze whole-genome and RNA sequencing for 1500 ALS/MND patients. Important analyses from whole-genome sequencing will include i) identifying rare variants in predicted regulatory sequences for exploration in Aim 3, ii) finding participants with mutations in known disease genes, and iii) investigating potentially oligogenic influences on disease. Analysis of the RNA-seq dataset for expression and splicing patterns that distinguish ALS/MND patients from controls or correlate with specific disease characteristics, thereby identifying potential biomarkers for diagnosis or sub-groups of similar patients. Aim 3: Integrate whole-genome sequence data with RNA-seq derived transcriptome data and clinical phenotypes for 1500 ALS/MND patients. Analyses of this integrated dataset will allow the common and rare candidate regulatory mutations identified in Aim 2 to be validated as eQTLs via detectable changes in corresponding gene(s) expression or novel splicing and to be correlated to aspects of disease phenotype.

Inclusion Criteria

Study participants meeting all of the following criteria will be eligible for enrollment in GTAC:

  1. Men or women of any race or ethnicity aged 18 or older
  2. Diagnosis of familial or sporadic ALS (definite, probable, or possible according to El Escorial Criteria, Appendix 1), or those with primary lateral sclerosis or progressive bulbar/muscular atrophy forms of motor neuron disease.  All-comers with ALS/MND should be enrolled without regard to familial vs sporadic or gene mutation status (i.e. participants with known gene mutations should still be enrolled), or phenotype. 
  3. Capable of providing informed consent and following study procedures (in the case that a subject lacks the ability to provide informed consent, informed consent will be sought from the subject’s surrogate representative).
  4. Willing to return to clinic site (or another participating center) for follow-up care.

Exclusion Criteria

Study participants meeting any of the following criteria during screening evaluation will be excluded from enrolling in GTAC:

  1. Invasive ventilation (i.e. tracheostomy) in place.
  2. Non-invasive ventilation dependent (defined as >22 hours per day)
  3. Pregnancy.
  4. Known HIV, chronic Hepatitis B, or Hepatitis C (because cells will be frozen down for future cell line generation).

NOTE: There is a preference against enrolling individuals already participating in either of two
specific studies: the ANSWER-ALS initiative (Jeff Rothstein and Clive Svensen, Co-PIs), or Project CReAte
(Michael Benatar, PI). This is intended to minimize duplication of efforts between GTAC and these
complementary studies, which in the future may undertake joint data analyses. If a given individual is not sure they are participating in one of these studies, it is fine to enroll them. Similarly, other genetic studies are not exclusionary, including Project MinE, ALS TDI, or other center-specific efforts. Participants in other types of studies (biomarkers, outcome, treatment) that may include some genetic components are still eligible for concurrent participation in GTAC. Each GTAC participant will have concurrent study participation documented in their study record.

In rare situations, the inclusion of an individual not meeting one of the above eligibility criteria (except pregnancy, HIV, Hepatitis B and Hepatitis C) may be scientifically merited (e.g. an unusual phenotype, disease course, or family history). The non-infectious and pregnancy inclusion and exclusion criteria were not select because of safety concerns, and therefore granting of exceptions on the other criteria should not create increased risk to participants. Exceptions will be considered on a case-by-case basis and must be approved in advance of enrollment by the CUMC-CC team.