AlzhEimer's Disease: Next Generation Researchers

 

 

The complexity of research into the genetic architecture of Alzheimer’s requires collaboration across dozens of institutions, including seasoned leaders and the faculty, postdoctoral fellows, and PhD candidates who make up their teams.

In collaboration with the Alzheimer’s Disease Genetics Consortium, we have developed a new multi-institutional seminar series highlighting next generation team members whose work contributes to the understanding of Alzheimer’s disease mechanism, with the goal of improving diagnosis and treatment.

 Each quarter, we highlight one of our colleague’s work.

Alessandra Chesi, PhD  

Dr. Chesi will present on Variant-to-gene mapping for brain-related traits and disorders on October 13, 2021.

 

 

Variant-to-gene mapping for brain-related traits and disorders

While genetic studies have revealed many variants in the human genome associated with brain-related diseases such as Alzheimer’s, the culprit effector genes (essential to design effective therapies) remain to be discovered. The main challenges are that 1) because of LD, GWAS identify “signals” and not the underlying causal variants and effector genes; 2) the majority of variants identified by GWAS reside in non-coding regions of the genome and are thought to regulate gene expression, often hundreds of kb away in linear distance and 3) gene expression regulation is exquisitely tissue and cell type specific. To tackle these issues, I propose a “variant-to-gene” mapping campaign leveraging high resolution promoter Capture C and/or Hi-C, plus ATAC-seq and ChIP-seq, in human iPSC-derived neural cell types (neurons, astrocytes and microglia, including co-cultures and brain organoids) from individuals and patients of different sex and ethnicity. This effort will provide targets for drug discovery and begin to address sex and ethnic differences in brain-related diseases, ultimately advancing the goals of precision medicine.

Alessandra Chesi, PhD

Assistant Professor

Department of Pathology and Laboratory Medicine

University of Pennsylvania

 

Alessandra Chesi, PhD, has focused her career thus far on neurodegenerative diseases. She brings to this work extensive experience in the generation and analysis of large datasets (including high resolution chromatin conformation capture techniques) with a focus on human genetic, epigenetic, and genomic investigations. 

As part of her postdoctoral training, she leveraged the power of yeast genetics to unveil the function of a Parkinson’s disease gene, PARK9, and she led a large exome-sequencing project of 47 sporadic ALS trios, identifying a set of potentially pathogenic de novo mutations enriched in chromatin regulator genes including neuronal chromatin remodeling complex (nBAF) component SS18L1.

While at the University of Pennsylvania and Stanford University, she set up bioinformatics pipelines (BWA, GATK, SAMtools, etc.) to analyze next-generation sequencing data. After joining the Center for Spatial and Functional Genomics at the Children’s Hospital of Philadelphia, she conducted genome wide association studies of different traits related to children’s health (bone mineral density and accrual, childhood obesity, early onset forms of type-2 diabetes) and developed and leveraged novel chromatin conformation capture techniques coupled with ATAC-seq to link known GWAS loci to their functional target gene(s).

In her own lab at Penn, she is now focusing on applying these and other cutting-edge genomic techniques to the study of neurodegenerative and brain-related disorders in human cell models.

She is part of the Penn Neurodegeneration Genomic Center (PNGC), a highly interdisciplinary and collaborative center with more than a dozen faculty members who specialize in neurodegenerative disorders and dementia, human genetics, genomics, bioinformatics, and biostatistics.

Find Dr. Chessi’s publications here

Anthony Griswold, PhD  

Dr. Griswold recently presented on Transcriptomic Approaches to Alzheimer Disease in Diverse Ancestral Populations. A video of his presentation is posted below.

 

 

Transcriptomic Approaches to Alzheimer Disease in Diverse Ancestral Populations.

Alzheimer Disease (AD), the leading cause of dementia in the elderly, occurs in all ethnic and racial groups. Although >20 bona fide susceptibility genetic loci have been associated with AD, much of the genetic influence on AD remains unknown. This is particularly true for diverse ethnic populations such as African Americans and Hispanics that are underrepresented in most genetic studies. Though we have begun to unravel some of the ancestry specific associated genetic risk of AD, identifying DNA variation is only one critical step in the complex underlying biology, since variants do not always provide direct information on the genes and mechanisms influenced. Here I will describe transcriptomic, epi-transcriptomic, and single cell RNA sequencing approaches towards understanding the etiology of AD in diverse populations. 

Anthony Griswold, PhD

Research Assistant Professor of Human Genetics

The Dr. John T. Macdonald Foundation Department of Human Genetics

John P. Hussman Institute for Human Genomics

Associate Director, Center for Genome Technology

University of Miami Miller School of Medicine

 

Dr. Griswold is a Research Assistant Professor in the Dr. John T. MacDonald Department of Human Genetics at the University of Miami Miller School of Medicine and in the John P. Hussman Institute for Human Genomics (HIHG). He serves as the leader of the Statistical and Bioinformatics Consulting Core in the Center for Epidemiology and Statistical Genetics at the HIHG where he manages a team of bioinformaticians and statistical geneticists.

His training is in molecular genetics with a recent focus in bioinformatics applied to running and developing analysis pipelines for massively parallel DNA sequencing analysis, RNA sequencing analysis, epigenomics, and comprehensive variant annotation and interpretation. His primary interest is in aiming to identify genetic risk for factors of complex phenotypes.

At the HIHG, he has been involved in several projects focusing on the underlying genetics of complex diseases including autism spectrum disorder (ASD) and Alzheimer’s disease in projects ranging from copy number variation analysis and identification of rare sequencing variants. His current work focuses on using sequencing technologies and bioinformatics approaches to identify genomic signatures of disease phenotypes.

Find Dr. Griswold’s publications here.

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Administratively housed at Case Western Reserve University with support from all participating academic institutions

Department of Population and Quantitative Health Sciences

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