Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number

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Vamsee Pillalamarri will discuss the impact of rare nuclear genetic variation on the number of copies of the mitochondrial genome, called mitochondrial DNA copy number (mtDNA-CN), an important biomarker for aging. Results from the study implicate an ancestral haplotype associated with increased mtDNA-CN, as well as highlight core processes involved with mtDNA replication and maintenance and enrichment of rare variant associations in Mendelian mtDNA depletion syndromes loci.

Learning Objectives

  • Highlight the association of mitochondrial DNA copy number with aging related traits and disease
  • Describe the use of whole-exome sequencing and genotyping data to estimate the number of copies of the mitochondrial genome in the UK Biobank
  • Perform an exome-wide association study of single-variant and gene-based groups of rare variants with mtDNA-CN
  • Identify 24 independent signals from 17 loci
  • Rare variants delineate a 1.2 Mb ancestral haplotype associated with increased mtDNA-CN, contrary to expectation that physically distant rare variants are in linkage equilibrium
  • mtDNA-CN associated rare variants are enriched in loci implicated in Mendelian mtDNA depletion syndromes


Vamsee Pillalamarri

PhD Candidate

Johns Hopkins University School of Medicine

Vamsee Pillalamarri is a PhD Candidate in Human Genetics at the Johns Hopkins University School of Medicine and is cross trained by the Johns Hopkins Bloomberg School of Public Health through the Maryland Genetics, Epidemiology, and Medicine training program. At Hopkins, with the supervision of Dr. Dan Arking, he investigates the role of mitochondrial DNA variation and copy number in complex traits and disease, and further studies the impact of complex genetic risk for autism spectrum disorder within general and admixed populations. Prior to his predoctoral studies, he earned bachelor’s and master’s degrees in Computer Science / Computational Biology from Carnegie Mellon University in Pittsburgh, PA, worked at the MIT Lincoln Laboratory in Boston, MA in forensic genetics, and served as a bioinformatics specialist and researcher at Massachusetts General Hospital within the lab of Dr. Michael Talkowski investigating the impact of complex structural variation for autism spectrum disorders.

 

Contact Vamsee Pillalamarri:

Twitter: @vkpillal

Email: vpillal1@jhmi.edu 

Dan E. Arking, PhD

Professor of Genetic Medicine

Johns Hopkins University School of Medicine

Dan E. Arking, Ph.D., is a Professor of Genetic Medicine at the Johns Hopkins University School of Medicine, and is the Deputy Director of Research in the Department of Genetic Medicine.  Dr. Arking earned his doctoral degree in human genetics from the Johns Hopkins University School of Medicine in 2001 and completed a postdoctoral fellowship at Johns Hopkins in the laboratory of Dr. Aravinda Chakravarti in 2005. Dr. Arking’s research focuses on identifying and characterizing genetic variants underlying complex human disease, with a specific focus on aging-related diseases and autism. Recent work has focused on the role of mitochondrial DNA variation in cardiovascular disease and overall mortality.  

Mike Bamshad, MD (Moderator)

Editor-in-Chief of HGG Advances

Chief of the Genetic Medicine Division of the Department of Pediatrics at Seattle Children’s Hospital, University of Washington (UW), Director of the Center for Clinical Genomics, Principal investigator the UW Center for Mendelian Genomics

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January Journal Club
01/11/2023 at 12:00 PM (EST)  |  Recorded On: 01/12/2023  |  30 minutes
01/11/2023 at 12:00 PM (EST)  |  Recorded On: 01/12/2023  |  30 minutes Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number