Megan Lancaster
Research Fellow, Vanderbilt University Medical Center
6 active projects
Cardiac PheWAS
Scientific Questions Being Studied
I study mutations, both common and rare, in genes known to influence heart disease. This workspace will be used for data exploration necessary to formalize specific research questions. The overall goal will be to improve our understanding of how specific mutations in genes influence heart disease, in order to better personalize diagnosis and clinical care for individuals with these mutations.
Project Purpose(s)
- Ancestry
Scientific Approaches
This work is focused on understanding how these mutations affect disease using statistical approaches suited for a large dataset such as All of Us. For example, one technique I plan to use is called a phenome-wide association study (PheWAS), which looks for statistical associations between mutations in a gene and different diseases across a large group of people.
Anticipated Findings
Broadly, I hope to better understand how specific mutations put an individual at risk for different diseases, with a focus on heart disease. Novel findings will contribute to the body of scientific knowledge in the field, and, importantly, can guide the clinical care of individuals and families who carry those mutations.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled Tier
Updated S1103Y sodium channel variant phenotypes
Scientific Questions Being Studied
The S1103Y variant in the cardiac sodium channel gene has been associated with type 3 congenital long QT syndrome and drug-induced long QT syndrome in several reports. However, this variant is too common in African American populations, with an allele frequency of 8.1%, to be highly pathogenic at baseline. Recent research in our lab in induced pluripotent stem cell derived cardiomyocytes has demonstrated that while this variant causes increased late sodium current, which should prolong the QT interval, the QT interval in these cells is not prolonged due to compensatory changes in other ion currents.
Project Purpose(s)
- Ancestry
Scientific Approaches
I plan to use the genomic array datasets in patients with African ancestry to find participants who are homozygous for the S1103Y variant, heterozygous for the variant, and those who do not carry the variant. I will then examine the association between S1103Y carrier status and ECG metrics such as the QT interval, as well as arrhythmia phenotypes in patients without diagnosed cardiovascular disease. I will then examine the contribution of this variant to a polygenic risk estimation of the QT interval, with attention to interaction with other ion channel protein-encoding and regulatory genes.
Anticipated Findings
I anticipate that the S1103Y variant will associate with QT interval prolongation and cases of drug-induced long QT, but with a smaller effect size than classic monogenic variant causes of long QT syndrome. I expect that the presence of the S1103Y variant will add to a polygenic risk assessment for long QT. I expect that the S1103Y variant will co-segregate with other cardiac ion channel-related genes.
Demographic Categories of Interest
- Race / Ethnicity
Data Set Used
Controlled TierDuplicate of How to Work with All of Us Genomic Data (Hail - Plink)(v6)
Scientific Questions Being Studied
Not applicable - these notebooks demonstrate example analysis how to use Hail and PLINK to perform genome-wide association studies using the All of Us genomic data and phenotypic data.
Project Purpose(s)
- Other Purpose (Demonstrate to the All of Us Researcher Workbench users how to get started with the All of Us genomic data and tools. It includes an overview of all the All of Us genomic data and shows some simple examples on how to use these data.)
Scientific Approaches
Not applicable - these notebooks demonstrate example analysis how to use Hail and PLINK to perform genome-wide association studies using the All of Us genomic data and phenotypic data.
Anticipated Findings
Not applicable - these notebooks demonstrate example analysis how to use Hail and PLINK to perform genome-wide association studies using the All of Us genomic data and phenotypic data.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierSMARD1
Scientific Questions Being Studied
We are studying the genetics of spinal muscular atrophy with respiratory distress type 1. This is a rare, inherited, severely debilitating disease with onset in infancy. While this is most commonly caused when an individual inherits a copy of the causative variant (mutation) from each parent (autosomal recessive inheritance), we hypothesize that inheritance can be more complex than this.
Project Purpose(s)
- Disease Focused Research (Spinal muscular atrophy with respiratory distress)
Scientific Approaches
We will use whole genome sequencing data from the All of Us to search for rare variants (mutations) in genes known and hypothesized to be causative in SMARD1. We will then compare this to the phenotypic data available in All of Us, looking specifically at neuromuscular symptoms and diagnoses.
Anticipated Findings
Understanding the genetics of SMARD1 will help us to better understand disease risk in individuals and their offspring, and to guide precision treatments.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierDuplicate of How to Work with All of Us Genomic Data (Hail - Plink)
Scientific Questions Being Studied
Validation of alpha 0 genomic data. Validation of alpha 0 genomic data. Validation of alpha 0 genomic data.
Project Purpose(s)
- Educational
Scientific Approaches
Validation of alpha 0 genomic data. Validation of alpha 0 genomic data. Validation of alpha 0 genomic data.
Anticipated Findings
Validation of alpha 0 genomic data. Validation of alpha 0 genomic data. Validation of alpha 0 genomic data.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierS1103Y sodium channel variant phenotypes
Scientific Questions Being Studied
The S1103Y variant in the cardiac sodium channel gene has been associated with type 3 congenital long QT syndrome and drug-induced long QT syndrome in several reports. However, this variant is too common in African American populations, with an allele frequency of 8.1%, to be highly pathogenic at baseline. Recent research in our lab in induced pluripotent stem cell derived cardiomyocytes has demonstrated that while this variant causes increased late sodium current, which should prolong the QT interval, the QT interval in these cells is not prolonged due to compensatory changes in other ion currents.
Project Purpose(s)
- Ancestry
Scientific Approaches
I plan to use the genomic array datasets in patients with African ancestry to find participants who are homozygous for the S1103Y variant, heterozygous for the variant, and those who do not carry the variant. I will then examine the association between S1103Y carrier status and ECG metrics such as the QT interval, as well as arrhythmia phenotypes in patients without diagnosed cardiovascular disease. I will then examine the contribution of this variant to a polygenic risk estimation of the QT interval, with attention to interaction with other ion channel protein-encoding and regulatory genes.
Anticipated Findings
I anticipate that the S1103Y variant will associate with QT interval prolongation and cases of drug-induced long QT, but with a smaller effect size than classic monogenic variant causes of long QT syndrome. I expect that the presence of the S1103Y variant will add to a polygenic risk assessment for long QT. I expect that the S1103Y variant will co-segregate with other cardiac ion channel-related genes.
Demographic Categories of Interest
- Race / Ethnicity
Data Set Used
Controlled TierRequest a Review of this Research Project
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